DNA double-strand break repair-pathway choice in somatic mammalian cells

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Abstract

The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context, these same repair functions can mediate chromosome rearrangements that underlie various human diseases, ranging from developmental disorders to cancer. The two major mechanisms of DSB repair in mammalian cells are non-homologous end joining (NHEJ) and homologous recombination. In this Review, we consider DSB repair-pathway choice in somatic mammalian cells as a series of ‘decision trees’, and explore how defective pathway choice can lead to genomic instability. Stalled, collapsed or broken DNA replication forks present a distinctive challenge to the DSB repair system. Emerging evidence suggests that the ‘rules’ governing repair-pathway choice at stalled replication forks differ from those at replication-independent DSBs.

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Fig. 1: The two major pathways of DNA double-strand break repair.
Fig. 2: Alternative DNA double-strand break repair pathways.
Fig. 3: A decision tree for DNA double-strand break repair.
Fig. 4: A decision tree for homologous recombination in somatic cells.
Fig. 5: RAD51 is an early responder at stalled replication forks.
Fig. 6: Single-strand annealing may function as a conservative repair pathway at stalled replication forks.

Change history

  • 09 August 2019

    The surname of the first author of ref.249, Jalan, was misspelled. The mistake has been corrected in the HTML and PDF versions of the article.

References

  1. 1.

    Ciccia, A. & Elledge, S. J. The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Paques, F. & Haber, J. E. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 63, 349–404 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Sung, P. & Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat. Rev. Mol. Cell Biol. 7, 739–750 (2006).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Symington, L. S. Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. Microbiol. Mol. Biol. Rev. 66, 630–670 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Prakash, R., Zhang, Y., Feng, W. & Jasin, M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb. Perspect. Biol. 7, a016600 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Hartlerode, A. J. & Scully, R. Mechanisms of double-strand break repair in somatic mammalian cells. Biochem. J. 423, 157–168 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Pannunzio, N. R., Watanabe, G. & Lieber, M. R. Nonhomologous DNA end joining for repair of DNA double-strand breaks. J. Biol. Chem. 293, 10512–10523 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Ferguson, D. O. et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc. Natl Acad. Sci. USA 97, 6630–6633 (2000).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Britton, S., Coates, J. & Jackson, S. P. A new method for high-resolution imaging of Ku foci to decipher mechanisms of DNA double-strand break repair. J. Cell Biol. 202, 579–595 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Gottlieb, T. M. & Jackson, S. P. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72, 131–142 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Nick McElhinny, S. A., Snowden, C. M., McCarville, J. & Ramsden, D. A. Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol. Cell. Biol. 20, 2996–3003 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Ahnesorg, P., Smith, P. & Jackson, S. P. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124, 301–313 (2006).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Buck, D. et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287–299 (2006).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Ochi, T. et al. DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185–188 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Zha, S. et al. ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks. Nature 469, 250–254 (2011).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kumar, V., Alt, F. W. & Frock, R. L. PAXX and XLF DNA repair factors are functionally redundant in joining DNA breaks in a G1-arrested progenitor B cell line. Proc. Natl Acad. Sci. USA 113, 10619–10624 (2016).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Graham, T. G., Walter, J. C. & Loparo, J. J. Two-stage synapsis of DNA ends during non-homologous end joining. Mol. Cell 61, 850–858 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Blackford, A. N. & Jackson, S. P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66, 801–817 (2017).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Stinson, B. M., Moreno, A. T., Walter, J. C. & Loparo, J. J. A mechanism to minimize errors during non-homologous end joining. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/563197v2 (2019).

  20. 20.

    Xie, A., Kwok, A. & Scully, R. Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat. Struct. Mol. Biol. 16, 814–818 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Dinkelmann, M. et al. Multiple functions of MRN in end-joining pathways during isotype class switching. Nat. Struct. Mol. Biol. 16, 808–813 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Williams, R. S. et al. Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell 135, 97–109 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Grundy, G. J. et al. APLF promotes the assembly and activity of non-homologous end joining protein complexes. EMBO J. 32, 112–125 (2013).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Macrae, C. J., McCulloch, R. D., Ylanko, J., Durocher, D. & Koch, C. A. APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation. DNA Repair 7, 292–302 (2008).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Rulten, S. L. et al. PARP-3 and APLF function together to accelerate nonhomologous end-joining. Mol. Cell 41, 33–45 (2011).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Arnoult, N. et al. Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN. Nature 549, 548–552 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Grundy, G. J. et al. The Ku-binding motif is a conserved module for recruitment and stimulation of non-homologous end-joining proteins. Nat. Commun. 7, 11242 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Liu, X. S. et al. LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair. Nat. Commun. 6, 8325 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Mimori, T. & Hardin, J. A. Mechanism of interaction between Ku protein and DNA. J. Biol. Chem. 261, 10375–10379 (1986).

    CAS  PubMed  Google Scholar 

  30. 30.

    Chang, H. H., Watanabe, G. & Lieber, M. R. Unifying the DNA end-processing roles of the artemis nuclease: Ku-dependent artemis resection at blunt DNA ends. J. Biol. Chem. 290, 24036–24050 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Chang, H. H. Y., Pannunzio, N. R., Adachi, N. & Lieber, M. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol. 18, 495–506 (2017).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Jiang, W. et al. Differential phosphorylation of DNA-PKcs regulates the interplay between end-processing and end-ligation during nonhomologous end-joining. Mol. Cell 58, 172–185 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Takata, M. et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 17, 5497–5508 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Kadyk, L. C. & Hartwell, L. H. Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae. Genetics 132, 387–402 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    San Filippo, J., Sung, P. & Klein, H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77, 229–257 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Symington, L. S. & Gautier, J. Double-strand break end resection and repair pathway choice. Annu. Rev. Genet. 45, 247–271 (2011).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Lee, J. H. & Paull, T. T. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304, 93–96 (2004).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Lee, J. H. & Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551–554 (2005).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Limbo, O. et al. Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. Mol. Cell 28, 134–146 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Sartori, A. A. et al. Human CtIP promotes DNA end resection. Nature 450, 509–514 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Lengsfeld, B. M., Rattray, A. J., Bhaskara, V., Ghirlando, R. & Paull, T. T. Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Mol. Cell 28, 638–651 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Cannavo, E. & Cejka, P. Sae2 promotes dsDNA endonuclease activity within Mre11-Rad50-Xrs2 to resect DNA breaks. Nature 514, 122–125 (2014).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Reginato, G., Cannavo, E. & Cejka, P. Physiological protein blocks direct the Mre11-Rad50-Xrs2 and Sae2 nuclease complex to initiate DNA end resection. Genes Dev. 31, 2325–2330 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Wang, W., Daley, J. M., Kwon, Y., Krasner, D. S. & Sung, P. Plasticity of the Mre11-Rad50-Xrs2-Sae2 nuclease ensemble in the processing of DNA-bound obstacles. Genes Dev. 31, 2331–2336 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Stafa, A., Donnianni, R. A., Timashev, L. A., Lam, A. F. & Symington, L. S. Template switching during break-induced replication is promoted by the Mph1 helicase in Saccharomyces cerevisiae. Genetics 196, 1017–1028 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Garcia, V., Phelps, S. E., Gray, S. & Neale, M. J. Bidirectional resection of DNA double-strand breaks by Mre11 and Exo1. Nature 479, 241–244 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Mimitou, E. P. & Symington, L. S. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455, 770–774 (2008).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Mimitou, E. P. & Symington, L. S. Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO J. 29, 3358–3369 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Nimonkar, A. V. et al. BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev. 25, 350–362 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Daley, J. M. et al. Enhancement of BLM-DNA2-mediated long-range DNA end resection by CtIP. Cell Rep. 21, 324–332 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Yang, H., Li, Q., Fan, J., Holloman, W. K. & Pavletich, N. P. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction. Nature 433, 653–657 (2005).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Jensen, R. B., Carreira, A. & Kowalczykowski, S. C. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467, 678–683 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Thorslund, T. et al. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 17, 1263–1265 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Anderson, D. G. & Kowalczykowski, S. C. The translocating RecBCD enzyme stimulates recombination by directing RecA protein onto ssDNA in a chi-regulated manner. Cell 90, 77–86 (1997).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Spies, M. & Kowalczykowski, S. C. The RecA binding locus of RecBCD is a general domain for recruitment of DNA strand exchange proteins. Mol. Cell 21, 573–580 (2006).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Krejci, L. et al. DNA helicase Srs2 disrupts the Rad51 presynaptic filament. Nature 423, 305–309 (2003).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Liu, J. et al. Rad51 paralogues Rad55-Rad57 balance the antirecombinase Srs2 in Rad51 filament formation. Nature 479, 245–248 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Heyer, W. D., Ehmsen, K. T. & Liu, J. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet. 44, 113–139 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Elango, R. et al. Break-induced replication promotes formation of lethal joint molecules dissolved by Srs2. Nat. Commun. 8, 1790 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Zhao, W. et al. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550, 360–365 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Chen, Z., Yang, H. & Pavletich, N. P. Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structures. Nature 453, 489–484 (2008).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    van der Heijden, T. et al. Homologous recombination in real time: DNA strand exchange by RecA. Mol. Cell 30, 530–538 (2008).

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    McVey, M., Khodaverdian, V. Y., Meyer, D., Cerqueira, P. G. & Heyer, W. D. Eukaryotic DNA polymerases in homologous recombination. Annu. Rev. Genet. 50, 393–421 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Kane, D. P., Shusterman, M., Rong, Y. & McVey, M. Competition between replicative and translesion polymerases during homologous recombination repair in Drosophila. PLOS Genet. 8, e1002659 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Hicks, W. M., Kim, M. & Haber, J. E. Increased mutagenesis and unique mutation signature associated with mitotic gene conversion. Science 329, 82–85 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    McVey, M., Adams, M., Staeva-Vieira, E. & Sekelsky, J. J. Evidence for multiple cycles of strand invasion during repair of double-strand gaps in Drosophila. Genetics 167, 699–705 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Smith, C. E., Llorente, B. & Symington, L. S. Template switching during break-induced replication. Nature 447, 102–105 (2007).

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Barber, L. J. et al. RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135, 261–271 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Whitby, M. C. The FANCM family of DNA helicases/translocases. DNA Repair 9, 224–236 (2010).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Xue, X., Sung, P. & Zhao, X. Functions and regulation of the multitasking FANCM family of DNA motor proteins. Genes Dev. 29, 1777–1788 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Vindigni, A. & Hickson, I. D. RecQ helicases: multiple structures for multiple functions? HFSP J. 3, 153–164 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Westmoreland, J. W. & Resnick, M. A. Coincident resection at both ends of random, gamma-induced double-strand breaks requires MRX (MRN), Sae2 (Ctp1), and Mre11-nuclease. PLOS Genet. 9, e1003420 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Bizard, A. H. & Hickson, I. D. The dissolution of double Holliday junctions. Cold Spring Harb. Perspect. Biol. 6, a016477 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Bennardo, N., Cheng, A., Huang, N. & Stark, J. M. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLOS Genet. 4, e1000110 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Mendez-Dorantes, C., Bhargava, R. & Stark, J. M. Repeat-mediated deletions can be induced by a chromosomal break far from a repeat, but multiple pathways suppress such rearrangements. Genes Dev. 32, 524–536 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Benitez, A. et al. FANCA promotes DNA double-strand break repair by catalyzing single-strand annealing and strand exchange. Mol. Cell 71, 621–628 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Yan, C. T. et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449, 478–482 (2007).

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Chan, S. H., Yu, A. M. & McVey, M. Dual roles for DNA polymerase theta in alternative end-joining repair of double-strand breaks in Drosophila. PLOS Genet. 6, e1001005 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Yu, A. M. & McVey, M. Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions. Nucleic Acids Res. 38, 5706–5717 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Mateos-Gomez, P. A. et al. The helicase domain of Polθ counteracts RPA to promote alt-NHEJ. Nat. Struct. Mol. Biol. 24, 1116–1123 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Kent, T., Chandramouly, G., McDevitt, S. M., Ozdemir, A. Y. & Pomerantz, R. T. Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase theta. Nat. Struct. Mol. Biol. 22, 230–237 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Shima, N., Munroe, R. J. & Schimenti, J. C. The mouse genomic instability mutation chaos1 is an allele of Polq that exhibits genetic interaction with Atm. Mol. Cell. Biol. 24, 10381–10389 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Koole, W. et al. A polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites. Nat. Commun. 5, 3216 (2014).

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Roerink, S. F., van Schendel, R. & Tijsterman, M. Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans. Genome Res. 24, 954–962 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Wyatt, D. W. et al. Essential roles for polymerase theta-mediated end joining in the repair of chromosome breaks. Mol. Cell 63, 662–673 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Ceccaldi, R. et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 518, 258–262 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Mateos-Gomez, P. A. et al. Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination. Nature 518, 254–257 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Boboila, C., Alt, F. W. & Schwer, B. Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks. Adv. Immunol. 116, 1–49 (2012).

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Yousefzadeh, M. J. et al. Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. PLOS Genet. 10, e1004654 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Zan, H. et al. Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination. Nat. Commun. 8, 14244 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Quinet, A., Lemacon, D. & Vindigni, A. Replication fork reversal: players and guardians. Mol. Cell 68, 830–833 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Neelsen, K. J. & Lopes, M. Replication fork reversal in eukaryotes: from dead end to dynamic response. Nat. Rev. Mol. Cell Biol. 16, 207–220 (2015).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Mayle, R. et al. Mus81 and converging forks limit the mutagenicity of replication fork breakage. Science 349, 742–747 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Willis, N. A. et al. Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 551, 590–595 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Nguyen, M. O., Jalan, M., Morrow, C. A., Osman, F. & Whitby, M. C. Recombination occurs within minutes of replication blockage by RTS1 producing restarted forks that are prone to collapse. eLife 4, e04539 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    Anand, R. P., Lovett, S. T. & Haber, J. E. Break-induced DNA replication. Cold Spring Harb. Perspect. Biol. 5, a010397 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Llorente, B., Smith, C. E. & Symington, L. S. Break-induced replication: what is it and what is it for? Cell Cycle 7, 859–864 (2008).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Saini, N. et al. Migrating bubble during break-induced replication drives conservative DNA synthesis. Nature 502, 389–392 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Roberts, S. A. et al. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol. Cell 46, 424–435 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Deem, A. et al. Break-induced replication is highly inaccurate. PLOS Biol. 9, e1000594 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Sakofsky, C. J. et al. Translesion polymerases drive microhomology-mediated break-induced replication leading to complex chromosomal rearrangements. Mol. Cell 60, 860–872 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Wilson, M. A. et al. Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration. Nature 502, 393–396 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Lydeard, J. R., Jain, S., Yamaguchi, M. & Haber, J. E. Break-induced replication and telomerase-independent telomere maintenance require Pol32. Nature 448, 820–823 (2007).

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Jain, S. et al. A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair. Genes Dev. 23, 291–303 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Heyer, W. D. Regulation of recombination and genomic maintenance. Cold Spring Harb. Perspect. Biol. 7, a016501 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Piazza, A. et al. Dynamic processing of displacement loops during recombinational DNA repair. Mol. Cell 73, 1255–1266 (2019).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Jain, S., Sugawara, N., Mehta, A., Ryu, T. & Haber, J. E. Sgs1 and Mph1 helicases enforce the recombination execution checkpoint during DNA double-strand break repair in Saccharomyces cerevisiae. Genetics 203, 667–675 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Mehta, A., Beach, A. & Haber, J. E. Homology requirements and competition between gene conversion and break-induced replication during double-strand break repair. Mol. Cell 65, 515–526 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Chandramouly, G. et al. BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids. Nat. Commun. 4, 2404 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Nagaraju, G., Hartlerode, A., Kwok, A., Chandramouly, G. & Scully, R. XRCC2 and XRCC3 regulate the balance between short- and long-tract gene conversions between sister chromatids. Mol. Cell. Biol. 29, 4283–4294 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Nagaraju, G., Odate, S., Xie, A. & Scully, R. Differential regulation of short- and long-tract gene conversion between sister chromatids by Rad51C. Mol. Cell. Biol. 26, 8075–8086 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Willis, N. A. et al. BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks. Nature 510, 556–559 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Costantino, L. et al. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343, 88–91 (2014).

    CAS  Article  Google Scholar 

  115. 115.

    Bhowmick, R., Minocherhomji, S. & Hickson, I. D. RAD52 facilitates mitotic DNA synthesis following replication stress. Mol. Cell 64, 1117–1126 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Minocherhomji, S. et al. Replication stress activates DNA repair synthesis in mitosis. Nature 528, 286–290 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Dilley, R. L. et al. Break-induced telomere synthesis underlies alternative telomere maintenance. Nature 539, 54–58 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Lee, J. A., Carvalho, C. M. & Lupski, J. R. A. DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Zhang, C. Z., Leibowitz, M. L. & Pellman, D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 27, 2513–2530 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Willis, N. A., Rass, E. & Scully, R. Deciphering the code of the cancer genome: mechanisms of chromosome rearrangement. Trends Cancer 1, 217–230 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Yu, Y. et al. Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks. Nature 564, 287–290 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Ira, G. & Haber, J. E. Characterization of RAD51-independent break-induced replication that acts preferentially with short homologous sequences. Mol. Cell. Biol. 22, 6384–6392 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Payen, C., Koszul, R., Dujon, B. & Fischer, G. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLOS Genet. 4, e1000175 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 124.

    Slack, A., Thornton, P. C., Magner, D. B., Rosenberg, S. M. & Hastings, P. J. On the mechanism of gene amplification induced under stress in Escherichia coli. PLOS Genet. 2, e48 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125.

    Hastings, P. J., Ira, G. & Lupski, J. R. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLOS Genet. 5, e1000327 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Piazza, A., Wright, W. D. & Heyer, W. D. Multi-invasions are recombination byproducts that induce chromosomal rearrangements. Cell 170, 760–773 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Simsek, D. & Jasin, M. Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation. Nat. Struct. Mol. Biol. 17, 410–416 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Guirouilh-Barbat, J. et al. 53BP1 protects against CtIP-dependent capture of ectopic chromosomal sequences at the junction of distant double-strand breaks. PLOS Genet. 12, e1006230 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. 129.

    Beck, C. R. et al. Megabase length hypermutation accompanies human structural variation at 17p11.2. Cell 176, 1310–1324 (2019).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Rowling, J. K. Harry Potter and the Philosopher’s Stone (Bloomsbury, 1997).

  131. 131.

    Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Roukos, V. et al. Spatial dynamics of chromosome translocations in living cells. Science 341, 660–664 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Okayasu, R. & Iliakis, G. Ionizing radiation induces two forms of interphase chromosome breaks in Chinese hamster ovary cells that rejoin with different kinetics and show different sensitivity to treatment in hypertonic medium or beta-araA. Radiat. Res. 136, 262–270 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Okayasu, R. & Iliakis, G. Evidence that the product of the xrs gene is predominantly involved in the repair of a subset of radiation-induced interphase chromosome breaks rejoining with fast kinetics. Radiat. Res. 138, 34–43 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. 135.

    Scully, R. et al. Genetic analysis of BRCA1 function in a defined tumor cell line. Mol. Cell 4, 1093–1099 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Lobrich, M. & Jeggo, P. A. Process of resection-dependent nonhomologous end joining involving the goddess Artemis. Trends Biochem. Sci. 42, 690–701 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    Sugawara, N., Wang, X. & Haber, J. E. In vivo roles of Rad52, Rad54, and Rad55 proteins in Rad51-mediated recombination. Mol. Cell 12, 209–219 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  138. 138.

    Haber, J. E. A. Life investigating pathways that repair broken chromosomes. Annu. Rev. Genet. 50, 1–28 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Cho, N. W., Dilley, R. L., Lampson, M. A. & Greenberg, R. A. Interchromosomal homology searches drive directional ALT telomere movement and synapsis. Cell 159, 108–121 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Shibata, A. et al. Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J. 30, 1079–1092 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Pierce, A. J., Hu, P., Han, M., Ellis, N. & Jasin, M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 15, 3237–3242 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Frank-Vaillant, M. & Marcand, S. Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol. Cell 10, 1189–1199 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. 143.

    Postow, L. Destroying the ring: freeing DNA from Ku with ubiquitin. FEBS Lett. 585, 2876–2882 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Aylon, Y., Liefshitz, B. & Kupiec, M. The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle. EMBO J. 23, 4868–4875 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Ira, G. et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431, 1011–1017 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Caspari, T., Murray, J. M. & Carr, A. M. Cdc2-cyclin B kinase activity links Crb2 and Rqh1-topoisomerase III. Genes Dev. 16, 1195–1208 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Huertas, P., Cortes-Ledesma, F., Sartori, A. A., Aguilera, A. & Jackson, S. P. CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455, 689–692 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Tomimatsu, N. et al. Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nat. Commun. 5, 3561 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  149. 149.

    Makharashvili, N. & Paull, T. T. CtIP: a DNA damage response protein at the intersection of DNA metabolism. DNA Repair 32, 75–81 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Anand, R., Ranjha, L., Cannavo, E. & Cejka, P. Phosphorylated CtIP functions as a co-factor of the MRE11-RAD50-NBS1 endonuclease in DNA end resection. Mol. Cell 64, 940–950 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Yu, X. & Chen, J. DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol. Cell. Biol. 24, 9478–9486 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Stark, J. M., Pierce, A. J., Oh, J., Pastink, A. & Jasin, M. Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol. Cell. Biol. 24, 9305–9316 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Polato, F. et al. CtIP-mediated resection is essential for viability and can operate independently of BRCA1. J. Exp. Med. 211, 1027–1036 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Zhou, Y., Caron, P., Legube, G. & Paull, T. T. Quantitation of DNA double-strand break resection intermediates in human cells. Nucleic Acids Res. 42, e19 (2014).

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Cruz-Garcia, A., Lopez-Saavedra, A. & Huertas, P. BRCA1 accelerates CtIP-mediated DNA-end resection. Cell Rep. 9, 451–459 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. 156.

    Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Cao, L. et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol. Cell 35, 534–541 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–695 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Nacson, J. et al. BRCA1 mutation-specific responses to 53BP1 loss-induced homologous recombination and PARP inhibitor resistance. Cell Rep. 24, 3513–3527 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Xie, A. et al. Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair. Mol. Cell 28, 1045–1057 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Zimmermann, M. & de Lange, T. 53BP1: pro choice in DNA repair. Trends Cell Biol. 24, 108–117 (2014).

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Chapman, J. R. et al. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol. Cell 49, 858–871 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Di Virgilio, M. et al. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339, 711–715 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  164. 164.

    Escribano-Diaz, C. et al. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol. Cell 49, 872–883 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  165. 165.

    Zimmermann, M., Lottersberger, F., Buonomo, S. B., Sfeir, A. & de Lange, T. 53BP1 regulates DSB repair using Rif1 to control 5΄ end resection. Science 339, 700–704 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Boersma, V. et al. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5΄ end resection. Nature 521, 537–540 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Xu, G. et al. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521, 541–544 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Callen, E. et al. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153, 1266–1280 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    He, Y. J. et al. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 563, 522–526 (2018).

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Becker, J. R. et al. The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. Nat. Commun. 9, 5406 (2018).

  171. 171.

    Gupta, R. et al. DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell 173, 972–988 (2018).

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Dev, H. et al. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat. Cell Biol. 20, 954–965 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Ghezraoui, H. et al. 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 560, 122–127 (2018).

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Mirman, Z. et al. 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature 560, 112–116 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Noordermeer, S. M. et al. The shieldin complex mediates 53BP1-dependent DNA repair. Nature 560, 117–121 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Tkac, J. et al. HELB is a feedback inhibitor of DNA end resection. Mol. Cell 61, 405–418 (2016).

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Orthwein, A. et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature 528, 422–426 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Duro, E. et al. Identification of the MMS22L-TONSL complex that promotes homologous recombination. Mol. Cell 40, 632–644 (2010).

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    O’Donnell, L. et al. The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination. Mol. Cell 40, 619–631 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. 180.

    Piwko, W. et al. RNAi-based screening identifies the Mms22L-Nfkbil2 complex as a novel regulator of DNA replication in human cells. EMBO J. 29, 4210–4222 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Piwko, W. et al. The MMS22L-TONSL heterodimer directly promotes RAD51-dependent recombination upon replication stress. EMBO J. 35, 2584–2601 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Saredi, G. et al. H4K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex. Nature 534, 714–718 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Rieder, C. L. & Cole, R. W. Entry into mitosis in vertebrate somatic cells is guarded by a chromosome damage checkpoint that reverses the cell cycle when triggered during early but not late prophase. J. Cell Biol. 142, 1013–1022 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Giunta, S., Belotserkovskaya, R. & Jackson, S. P. DNA damage signaling in response to double-strand breaks during mitosis. J. Cell Biol. 190, 197–207 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Lee, D. H. et al. Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks. Mol. Cell 54, 512–525 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Orthwein, A. et al. Mitosis inhibits DNA double-strand break repair to guard against telomere fusions. Science 344, 189–193 (2014).

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Goodarzi, A. A. et al. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell 31, 167–177 (2008).

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Aymard, F. et al. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat. Struct. Mol. Biol. 21, 366–374 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Daugaard, M. et al. LEDGF (p75) promotes DNA-end resection and homologous recombination. Nat. Struct. Mol. Biol. 19, 803–810 (2012).

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Gardini, A., Baillat, D., Cesaroni, M. & Shiekhattar, R. Genome-wide analysis reveals a role for BRCA1 and PALB2 in transcriptional co-activation. EMBO J. 33, 890–905 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Garcia-Muse, T. & Aguilera, A. Transcription-replication conflicts: how they occur and how they are resolved. Nat. Rev. Mol. Cell Biol. 17, 553–563 (2016).

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    Hill, S. J. et al. Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev. 28, 1957–1975 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. 193.

    Hatchi, E. et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57, 636–647 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Kim, J. et al. Replication stress shapes a protective chromatin environment across fragile genomic regions. Mol. Cell 69, 36–47 (2018).

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    Seeber, A. & Gasser, S. M. Chromatin organization and dynamics in double-strand break repair. Curr. Opin. Genet. Dev. 43, 9–16 (2017).

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Soutoglou, E. et al. Positional stability of single double-strand breaks in mammalian cells. Nat. Cell Biol. 9, 675–682 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Aten, J. A. et al. Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 303, 92–95 (2004).

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Dimitrova, N., Chen, Y. C., Spector, D. L. & de Lange, T. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 456, 524–528 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Lottersberger, F., Karssemeijer, R. A., Dimitrova, N. & de Lange, T. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 163, 880–893 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Amaral, N., Ryu, T., Li, X. & Chiolo, I. Nuclear dynamics of heterochromatin repair. Trends Genet. 33, 86–100 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. 201.

    Chiolo, I. et al. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144, 732–744 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Tsouroula, K. et al. Temporal and spatial uncoupling of DNA double strand break repair pathways within mammalian heterochromatin. Mol. Cell 63, 293–305 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  203. 203.

    Lopes, M., Foiani, M. & Sogo, J. M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21, 15–27 (2006).

    CAS  PubMed  Article  Google Scholar 

  204. 204.

    Zeman, M. K. & Cimprich, K. A. Causes and consequences of replication stress. Nat. Cell Biol. 16, 2–9 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205.

    Berti, M. & Vindigni, A. Replication stress: getting back on track. Nat. Struct. Mol. Biol. 23, 103–109 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Marians, K. J. Lesion bypass and the reactivation of stalled replication forks. Annu. Rev. Biochem. 87, 217–238 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Giannattasio, M. et al. Visualization of recombination-mediated damage bypass by template switching. Nat. Struct. Mol. Biol. 21, 884–892 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. 208.

    Costanzo, V. et al. An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol. Cell 11, 203–213 (2003).

    CAS  PubMed  Article  Google Scholar 

  209. 209.

    Cimprich, K. A. & Cortez, D. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 9, 616–627 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Wu, R. A. et al. TRAIP is a master regulator of DNA interstrand crosslink repair. Nature 567, 267–272 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  211. 211.

    Long, D. T., Raschle, M., Joukov, V. & Walter, J. C. Mechanism of RAD51-dependent DNA interstrand cross-link repair. Science 333, 84–87 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. 212.

    Willis, N. A., Panday, A., Duffey, E. E. & Scully, R. Rad51 recruitment and exclusion of non-homologous end joining during homologous recombination at a Tus/Ter mammalian replication fork barrier. PLOS Genet. 14, e1007486 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  213. 213.

    Ait Saada, A., Lambert, S. A. E. & Carr, A. M. Preserving replication fork integrity and competence via the homologous recombination pathway. DNA Repair 71, 135–147 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  214. 214.

    Raschle, M. et al. Mechanism of replication-coupled DNA interstrand crosslink repair. Cell 134, 969–980 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    Amunugama, R. et al. Replication fork reversal during DNA interstrand crosslink repair requires CMG unloading. Cell Rep. 23, 3419–3428 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  216. 216.

    Klein Douwel, D. et al. XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol. Cell 54, 460–471 (2014).

    CAS  PubMed  Article  Google Scholar 

  217. 217.

    Knipscheer, P. et al. The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science 326, 1698–1701 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Deng, L. et al. Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements. Mol. Cell 73, 915–929 (2019).

    CAS  PubMed  Article  Google Scholar 

  219. 219.

    Sogo, J. M., Lopes, M. & Foiani, M. Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297, 599–602 (2002).

    CAS  Article  Google Scholar 

  220. 220.

    Moldovan, G. L. et al. Inhibition of homologous recombination by the PCNA-interacting protein PARI. Mol. Cell 45, 75–86 (2012).

    CAS  PubMed  Article  Google Scholar 

  221. 221.

    Dungrawala, H. et al. RADX promotes genome stability and modulates chemosensitivity by regulating RAD51 at replication forks. Mol. Cell 67, 374–386 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  222. 222.

    Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. 223.

    Schlacher, K., Wu, H. & Jasin, M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22, 106–116 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Kolinjivadi, A. M. et al. Smarcal1-mediated fork reversal triggers Mre11-dependent degradation of nascent DNA in the absence of Brca2 and stable Rad51 nucleofilaments. Mol. Cell 67, 867–881 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  225. 225.

    Taglialatela, A. et al. Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers. Mol. Cell 68, 414–430 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  226. 226.

    Vujanovic, M. et al. Replication fork slowing and reversal upon DNA damage require PCNA polyubiquitination and ZRANB3 DNA translocase activity. Mol. Cell 67, 882–890 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  227. 227.

    Duxin, J. P. & Walter, J. C. What is the DNA repair defect underlying Fanconi anemia? Curr. Opin. Cell Biol. 37, 49–60 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  228. 228.

    Huang, J. et al. The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks. Mol. Cell 52, 434–446 (2013).

    CAS  PubMed  Article  Google Scholar 

  229. 229.

    Semlow, D. R., Zhang, J., Budzowska, M., Drohat, A. C. & Walter, J. C. Replication-dependent unhooking of DNA interstrand cross-links by the NEIL3 glycosylase. Cell 167, 498–511 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  230. 230.

    Zhang, J. et al. DNA interstrand cross-link repair requires replication-fork convergence. Nat. Struct. Mol. Biol. 22, 242–247 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. 231.

    Lambert, S. et al. Homologous recombination restarts blocked replication forks at the expense of genome rearrangements by template exchange. Mol. Cell 39, 346–359 (2010).

    CAS  PubMed  Article  Google Scholar 

  232. 232.

    Ceccaldi, R., Sarangi, P. & D’Andrea, A. D. The Fanconi anaemia pathway: new players and new functions. Nat. Rev. Mol. Cell Biol. 17, 337–349 (2016).

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Nakanishi, K. et al. Homology-directed Fanconi anemia pathway cross-link repair is dependent on DNA replication. Nat. Struct. Mol. Biol. 18, 500–503 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    Foster, S. S., Balestrini, A. & Petrini, J. H. Functional interplay of the Mre11 nuclease and Ku in the response to replication-associated DNA damage. Mol. Cell. Biol. 31, 4379–4389 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  235. 235.

    Balestrini, A. et al. The Ku heterodimer and the metabolism of single-ended DNA double-strand breaks. Cell Rep. 3, 2033–2045 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  236. 236.

    Chanut, P., Britton, S., Coates, J., Jackson, S. P. & Calsou, P. Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks. Nat. Commun. 7, 12889 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  237. 237.

    Balmus, G. et al. ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks. Nat. Commun. 10, 87 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  238. 238.

    Vriend, L. E. et al. Distinct genetic control of homologous recombination repair of Cas9-induced double-strand breaks, nicks and paired nicks. Nucleic Acids Res. 44, 5204–5217 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  239. 239.

    Wang, A. T. et al. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol. Cell 59, 478–490 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  240. 240.

    Zellweger, R. et al. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J. Cell Biol. 208, 563–579 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  241. 241.

    Bhat, K. P. & Cortez, D. RPA and RAD51: fork reversal, fork protection, and genome stability. Nat. Struct. Mol. Biol. 25, 446–453 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  242. 242.

    Frock, R. L. et al. Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat. Biotechnol. 33, 179–186 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  243. 243.

    Tubbs, A. et al. Dual roles of poly(dA:dT) tracts in replication initiation and fork collapse. Cell 174, 1127–1142 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  244. 244.

    Shastri, N. et al. Genome-wide identification of structure-forming repeats as principal sites of fork collapse upon ATR inhibition. Mol. Cell 72, 222–238 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  245. 245.

    Petermann, E., Orta, M. L., Issaeva, N., Schultz, N. & Helleday, T. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol. Cell 37, 492–502 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  246. 246.

    Heller, R. C. & Marians, K. J. Replisome assembly and the direct restart of stalled replication forks. Nat. Rev. Mol. Cell Biol. 7, 932–943 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  247. 247.

    Carr, A. M. & Lambert, S. Replication stress-induced genome instability: the dark side of replication maintenance by homologous recombination. J. Mol. Biol. 425, 4733–4744 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  248. 248.

    Lambert, S., Watson, A., Sheedy, D. M., Martin, B. & Carr, A. M. Gross chromosomal rearrangements and elevated recombination at an inducible site-specific replication fork barrier. Cell 121, 689–702 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  249. 249.

    Jalan, M., Oehler, J., Morrow, C. A., Osman, F. & Whitby, M. C. Factors affecting template switch recombination associated with restarted DNA replication. eLife 8, e41697 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  250. 250.

    Sotiriou, S. K. et al. Mammalian RAD52 functions in break-induced replication repair of collapsed DNA replication forks. Mol. Cell 64, 1127–1134 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  251. 251.

    Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  252. 252.

    Menghi, F. et al. The tandem duplicator phenotype as a distinct genomic configuration in cancer. Proc. Natl Acad. Sci. USA 113, E2373–E2382 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  253. 253.

    Clouaire, T. & Legube, G. A. Snapshot on the cis chromatin response to DNA double-strand breaks. Trends Genet. 35, 330–345 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  254. 254.

    Price, B. D. & D’Andrea, A. D. Chromatin remodeling at DNA double-strand breaks. Cell 152, 1344–1354 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  255. 255.

    Bass, T. E. et al. ETAA1 acts at stalled replication forks to maintain genome integrity. Nat. Cell Biol. 18, 1185–1195 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  256. 256.

    Feng, S. et al. Ewing tumor-associated antigen 1 interacts with replication protein A to promote restart of stalled replication forks. J. Biol. Chem. 291, 21956–21962 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  257. 257.

    Haahr, P. et al. Activation of the ATR kinase by the RPA-binding protein ETAA1. Nat. Cell Biol. 18, 1196–1207 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  258. 258.

    Cortez, D., Guntuku, S., Qin, J. & Elledge, S. J. ATR and ATRIP: partners in checkpoint signaling. Science 294, 1713–1716 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  259. 259.

    Zou, L. & Elledge, S. J. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542–1548 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  260. 260.

    Scully, R. & Xie, A. Double strand break repair functions of histone H2AX. Mut. Res. 750, 5–14 (2013).

    CAS  Article  Google Scholar 

  261. 261.

    Stucki, M. & Jackson, S. P. γH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. DNA Repair 5, 534–543 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  262. 262.

    Helmink, B. A. et al. H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes. Nature 469, 245–249 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  263. 263.

    Messick, T. E. & Greenberg, R. A. The ubiquitin landscape at DNA double-strand breaks. J. Cell Biol. 187, 319–326 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  264. 264.

    Jackson, S. P. & Durocher, D. Regulation of DNA damage responses by ubiquitin and SUMO. Mol. Cell 49, 795–807 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  265. 265.

    Lukas, J., Lukas, C. & Bartek, J. More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat. Cell Biol. 13, 1161–1169 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  266. 266.

    Doil, C. et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136, 435–446 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  267. 267.

    Stewart, G. S. et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420–434 (2009).

    CAS  Article  PubMed  Google Scholar 

  268. 268.

    Feng, L., Huang, J. & Chen, J. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev. 23, 719–728 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  269. 269.

    Shao, G. et al. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev. 23, 740–754 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  270. 270.

    Hu, Y. et al. RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. Genes Dev. 25, 685–700 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  271. 271.

    Coleman, K. A. & Greenberg, R. A. The BRCA1-RAP80 complex regulates DNA repair mechanism utilization by restricting end resection. J. Biol. Chem. 286, 13669–13680 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  272. 272.

    Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  273. 273.

    Nakamura, K. et al. Genetic dissection of vertebrate 53BP1: a major role in non-homologous end joining of DNA double strand breaks. DNA Repair 5, 741–749 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  274. 274.

    Polo, S. E. & Jackson, S. P. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409–433 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  275. 275.

    Nakamura, K. et al. Regulation of homologous recombination by RNF20-dependent H2B ubiquitination. Mol. Cell 41, 515–528 (2011).

    CAS  PubMed  Article  Google Scholar 

  276. 276.

    Moyal, L. et al. Requirement of ATM-dependent monoubiquitylation of histone H2B for timely repair of DNA double-strand breaks. Mol. Cell 41, 529–542 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  277. 277.

    Chapman, J. R., Sossick, A. J., Boulton, S. J. & Jackson, S. P. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J. Cell Sci. 125, 3529–3534 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  278. 278.

    Tang, J. et al. Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nat. Struct. Mol. Biol. 20, 317–325 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  279. 279.

    Jacquet, K. et al. The TIP60 complex regulates bivalent chromatin recognition by 53BP1 through direct H4K20me binding and H2AK15 acetylation. Mol. Cell 62, 409–421 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  280. 280.

    Densham, R. M. et al. Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat. Struct. Mol. Biol. 23, 647–655 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  281. 281.

    Drane, P. et al. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 543, 211–216 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The authors thank Johannes Walter, Joe Loparo, Andre Nussenzweig, Stephen Jackson, Edison Liu, David Cortez, Agata Smogorzewska and the Scully laboratory members for helpful discussions and for sharing unpublished research findings. This work was supported by awards R01CA095175, R01CA217991, OC160440, BC160172P1 and R21ES027776 (to R.S.) and P50CA168504 (to N.A.W.).

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Nature Reviews Molecular Cell Biology thanks P. Čejka and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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R.S., A.P., R.E. and N.A.W. contributed to researching the article; all authors contributed to discussion of the content; R.S. and N.A.W. wrote the article; all authors contributed to reviewing and editing the article before submission.

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Correspondence to Ralph Scully or Nicholas A. Willis.

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Glossary

One-ended breaks

Solitary DNA ends that lack an immediate second DNA end for rejoining or annealing.

Stalled replication forks

Replication forks that have been arrested at DNA damage sites or because of other causes.

Synapse

A DNA and protein complex in which two DNA molecules are brought into close proximity with the assistance of their associated proteins.

PARP inhibitors

Inhibitors of poly(ADP-ribose) polymerase (PARP) (especially PARP1) induce synthetic lethality in homologous recombination mutant cells through an unresolved mechanism that involves trapping of PARP1 on DNA.

χ sequences

Short sequences in bacterial genomes that serve as ‘hotspots’ for recombination; no equivalent has been identified in vertebrates.

Gene conversion

The transfer of genetic material from a donor sequence to a homologous acceptor during homologous recombination.

Translesion DNA polymerases

Specialized DNA polymerases that can traverse a damaged and unreadable DNA template.

Holliday junction

A four-way branched DNA structure that can mediate reciprocal exchanges between two homologous DNA molecules.

Non-crossover

A repair pathway that does not result in crossing over.

Crossing over

The exchange of genetic material between two homologous chromosomes.

Broken replication forks

Stalled replication forks that have lost their branched DNA structure due to interruption of both DNA strands of at least one sister chromatid.

Collapsed replication forks

Stalled replication forks that have lost the capacity to perform DNA synthesis due to disassembly of the replisome.

Replication restart

Resumption of DNA synthesis at a stalled fork; may be mediated by conventional semiconservative DNA synthesis or by error-prone mechanisms.

Migrating bubble

DNA synthesis mechanism of long-tract gene conversion and break-induced replication.

Daughter strand gaps

(DSGs). Post-replicative DNA single-strand gaps caused by interruption of the synthesis of the nascent daughter strand.

Chromothripsis

Localized chromosome shattering and repair that occurs as a one-off catastrophe, generating an alternating copy number profile at the affected locus.

Chromoplexy

A closed chain of linked translocations, with little or no copy number alteration, observed in some cancers.

Prophase

The first stage of mitosis, during which chromosomes begin to condense.

Hemicatenanes

Topological entanglements of two double-stranded DNA molecules, in which one strand of each duplex passes between the two strands of the other duplex.

Fork reversal

A stalled and collapsed replication fork in which reannealing of the parental strands has moved the branch-point of the fork backwards, extruding the annealed nascent strands to form a ‘chicken foot’ four-way DNA junction.

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Scully, R., Panday, A., Elango, R. et al. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol 20, 698–714 (2019). https://doi.org/10.1038/s41580-019-0152-0

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