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Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Nature Reviews Molecular Cell Biology volume 23, pages 125–140 (2022)Cite this article

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Abstract

Cellular pathways that repair chromosomal double-strand breaks (DSBs) have pivotal roles in cell growth, development and cancer. These DSB repair pathways have been the target of intensive investigation, but one pathway — alternative end joining (a-EJ) — has long resisted elucidation. In this Review, we highlight recent progress in our understanding of a-EJ, especially the assignment of DNA polymerase theta (Polθ) as the predominant mediator of a-EJ in most eukaryotes, and discuss a potential molecular mechanism by which Polθ-mediated end joining (TMEJ) occurs. We address possible cellular functions of TMEJ in resolving DSBs that are refractory to repair by non-homologous end joining (NHEJ), DSBs generated following replication fork collapse and DSBs present owing to stalling of repair by homologous recombination. We also discuss how these context-dependent cellular roles explain how TMEJ can both protect against and cause genome instability, and the emerging potential of Polθ as a therapeutic target in cancer.

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Fig. 1: DNA double-strand break repair pathways and microhomology use during end joining.
Fig. 2: Molecular mechanism of Polθ-mediated end joining.
Fig. 3: Biological roles of Polθ-mediated end joining.
Fig. 4: Regulation of Polθ-mediated end joining through end resection.
Fig. 5: Translation of Polθ inhibitors into the clinic.

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References

  1. Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20, 698–714 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Boulton, S. J. & Jackson, S. P. Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J. 15, 5093–5103 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kabotyanski, E. B., Gomelsky, L., Han, J.-O., Roth, D. B. & Stamato, T. D. Double-strand break repair in Ku86-and XRCC4-deficient cells. Nucleic acids Res. 26, 5333–5342 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Liang, F. & Jasin, M. Ku80-deficient cells exhibit excess degradation of extrachromosomal DNA. J. Biol. Chem. 271, 14405–14411 (1996).

    CAS  PubMed  Google Scholar 

  5. Bothmer, A. et al. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J. Exp. Med. 207, 855–865 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Deriano, L., Stracker, T. H., Baker, A., Petrini, J. H. & Roth, D. B. Roles for NBS1 in alternative nonhomologous end-joining of V(D)J recombination intermediates. Mol. Cell 34, 13–25 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee-Theilen, M., Matthews, A. J., Kelly, D., Zheng, S. & Chaudhuri, J. CtIP promotes microhomology-mediated alternative end joining during class-switch recombination. Nat. Struct. Mol. Biol. 18, 75–79 (2011).

    CAS  PubMed  Google Scholar 

  8. Ma, J. L., Kim, E. M., Haber, J. E. & Lee, S. E. Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Mol. Cell Biol. 23, 8820–8828 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Rahal, E. A. et al. ATM regulates Mre11-dependent DNA end-degradation and microhomology-mediated end joining. Cell Cycle 9, 2866–2877 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Truong, L. N. et al. Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc. Natl Acad. Sci. USA 110, 7720–7725 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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  Google Scholar 

  12. Yun, M. H. & Hiom, K. CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459, 460–463 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang, Y. & Jasin, M. An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nat. Struct. Mol. Biol. 18, 80–84 (2011).

    CAS  PubMed  Google Scholar 

  14. 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  Google Scholar 

  15. Beall, E. L. & Rio, D. C. Drosophila P-element transposase is a novel site-specific endonuclease. Genes Dev. 11, 2137–2151 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 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  Google Scholar 

  17. 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  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  19. Thyme, S. B. & Schier, A. F. Polq-mediated end joining is essential for surviving DNA double-strand breaks during early zebrafish development. Cell Rep. 15, 707–714 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. van Schendel, R., Roerink, S. F., Portegijs, V., van den Heuvel, S. & Tijsterman, M. Polymerase theta is a key driver of genome evolution and of CRISPR/Cas9-mediated mutagenesis. Nat. Commun. 6, 7394 (2015).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Saito, S., Maeda, R. & Adachi, N. Dual loss of human POLQ and LIG4 abolishes random integration. Nat. Commun. 8, 16112 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zelensky, A. N., Schimmel, J., Kool, H., Kanaar, R. & Tijsterman, M. Inactivation of Pol theta and C-NHEJ eliminates off-target integration of exogenous DNA. Nat. Commun. 8, 66 (2017).

    PubMed  PubMed Central  Google Scholar 

  24. 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  Google Scholar 

  25. Seki, M., Marini, F. & Wood, R. D. POLQ (Pol theta), a DNA polymerase and DNA-dependent ATPase in human cells. Nucleic Acids Res. 31, 6117–6126 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Takata, K. I. et al. Analysis of DNA polymerase nu function in meiotic recombination, immunoglobulin class-switching, and DNA damage tolerance. PLoS Genet. 13, e1006818 (2017).

    PubMed  PubMed Central  Google Scholar 

  27. Yousefzadeh, M. J. & Wood, R. D. DNA polymerase POLQ and cellular defense against DNA damage. DNA Repair 12, 1–9 (2013).

    CAS  PubMed  Google Scholar 

  28. Black, S. J. et al. Molecular basis of microhomology-mediated end-joining by purified full-length Poltheta. Nat. Commun. 10, 4423 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hogg, M., Seki, M., Wood, R. D., Doublie, S. & Wallace, S. S. Lesion bypass activity of DNA polymerase theta (POLQ) is an intrinsic property of the pol domain and depends on unique sequence inserts. J. Mol. Biol. 405, 642–652 (2011).

    CAS  PubMed  Google Scholar 

  30. Wood, R. D. & Doublie, S. DNA polymerase theta (POLQ), double-strand break repair, and cancer. DNA Repair 44, 22–32 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Zahn, K. E., Averill, A. M., Aller, P., Wood, R. D. & Doublie, S. Human DNA polymerase theta grasps the primer terminus to mediate DNA repair. Nat. Struct. Mol. Biol. 22, 304–311 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zahn, K. E., Jensen, R. B., Wood, R. D. & Doublie, S. Human DNA polymerase theta harbors DNA end-trimming activity critical for DNA repair. Mol. Cell 81, 1534–1547 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Newman, J. A., Cooper, C. D. O., Aitkenhead, H. & Gileadi, O. Structure of the helicase domain of DNA polymerase theta reveals a possible role in the microhomology-mediated end-joining pathway. Structure 23, 2319–2330 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ozdemir, A. Y., Rusanov, T., Kent, T., Siddique, L. A. & Pomerantz, R. T. Polymerase theta-helicase efficiently unwinds DNA and RNA-DNA hybrids. J. Biol. Chem. 293, 5259–5269 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Bazzano, D., Lomonaco, S. & Wilson, T. E. Mapping yeast mitotic 5’ resection at base resolution reveals the sequence and positional dependence of nucleases in vivo. Nucleic Acids Res. https://doi.org/10.1093/nar/gkab597 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  38. Zhu, Z., Chung, W. H., Shim, E. Y., Lee, S. E. & Ira, G. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134, 981–994 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Eccleston, J., Yan, C., Yuan, K., Alt, F. W. & Selsing, E. Mismatch repair proteins MSH2, MLH1, and EXO1 are important for class-switch recombination events occurring in B cells that lack nonhomologous end joining. J. Immunol. 186, 2336–2343 (2011).

    CAS  PubMed  Google Scholar 

  40. Howard, S. M., Yanez, D. A. & Stark, J. M. DNA damage response factors from diverse pathways, including DNA crosslink repair, mediate alternative end joining. PLoS Genet. 11, e1004943 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. 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  Google Scholar 

  42. Wang, Z. et al. DNA polymerase theta (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. J. Biol. Chem. 294, 3909–3919 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kais, Z. et al. FANCD2 maintains fork stability in BRCA1/2-deficient tumors and promotes alternative end-joining DNA repair. Cell Rep. 15, 2488–2499 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Audebert, M., Salles, B. & Calsou, P. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J. Biol. Chem. 279, 55117–55126 (2004).

    CAS  PubMed  Google Scholar 

  45. Mansour, W. Y., Rhein, T. & Dahm-Daphi, J. The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies. Nucleic Acids Res. 38, 6065–6077 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang, M. et al. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res. 34, 6170–6182 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Caldecott, K. W. XRCC1 protein; form and function. DNA Repair 81, 102664 (2019).

    CAS  PubMed  Google Scholar 

  48. Yu, W. et al. Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ. Nat. Commun. 11, 5239 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zatreanu, D. et al. Poltheta inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat. Commun. 12, 3636 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhou, J. et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat. Cancer 2, 598–610 (2021).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Deng, S. K., Gibb, B., de Almeida, M. J., Greene, E. C. & Symington, L. S. RPA antagonizes microhomology-mediated repair of DNA double-strand breaks. Nat. Struct. Mol. Biol. 21, 405–412 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Shukla, V. et al. HMCES functions in the alternative end-joining pathway of the DNA DSB repair during class switch recombination in B cells. Mol. Cell 77, 384–394 e384 (2020).

    CAS  PubMed  Google Scholar 

  54. Hussmann, J. A. et al. Mapping the genetic landscape of DNA double-strand break repair. bioRxiv https://doi.org/10.1101/2021.06.14.448344 (2021).

    Article  Google Scholar 

  55. van Schendel, R., Romeijn, R., Buijs, H. & Tijsterman, M. Preservation of lagging strand integrity at sites of stalled replication by Pol alpha-primase and 9-1-1 complex. Sci Adv 7, eabf2278 (2021).

    PubMed  PubMed Central  Google Scholar 

  56. Carvajal-Garcia, J. et al. Mechanistic basis for microhomology identification and genome scarring by polymerase theta. Proc. Natl Acad. Sci. USA 117, 8476–8485 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. He, P. & Yang, W. Template and primer requirements for DNA Pol theta-mediated end joining. Proc. Natl Acad. Sci. USA 115, 7747–7752 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang, Y., Davis, L. & Maizels, N. Pathways and signatures of mutagenesis at targeted DNA nicks. PLoS Genet. 17, e1009329 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kamp, J. A., van Schendel, R., Dilweg, I. W. & Tijsterman, M. BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining. Nat. Commun. 11, 3615 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. van Schendel, R., van Heteren, J., Welten, R. & Tijsterman, M. Genomic scars generated by polymerase theta reveal the versatile mechanism of alternative end-joining. PLoS Genet. 12, e1006368 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. Feng, W. et al. Genetic determinants of cellular addiction to DNA polymerase theta. Nat. Commun. 10, 4286 (2019).

    PubMed  PubMed Central  Google Scholar 

  62. Schimmel, J., Kool, H., van Schendel, R. & Tijsterman, M. Mutational signatures of non-homologous and polymerase theta-mediated end-joining in embryonic stem cells. EMBO J. 36, 3634–3649 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Kosicki, M., Allen, F. & Bradley, A. Cas9-induced large deletions and small indels are controlled in a convergent fashion. bioRxiv https://doi.org/10.1101/2020.08.05.216739 (2020).

    Article  Google Scholar 

  64. Hwang, T. et al. Defining the mutation signatures of DNA polymerase theta in cancer genomes. NAR Cancer 2, zcaa017 (2020).

    PubMed  PubMed Central  Google Scholar 

  65. Khodaverdian, V. Y. et al. Secondary structure forming sequences drive SD-MMEJ repair of DNA double-strand breaks. Nucleic Acids Res. 45, 12848–12861 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. van Kregten, M. et al. T-DNA integration in plants results from polymerase-theta-mediated DNA repair. Nat. Plants 2, 16164 (2016).

    PubMed  Google Scholar 

  67. Schimmel, J., van Schendel, R., den Dunnen, J. T. & Tijsterman, M. Templated insertions: a smoking gun for polymerase theta-mediated end joining. Trends Genet. 35, 632–644 (2019).

    CAS  PubMed  Google Scholar 

  68. Morton, L. M. et al. Radiation-related genomic profile of papillary thyroid cancer after the Chernobyl accident. Science 372, eabg2538 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 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  Google Scholar 

  70. 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  Google Scholar 

  71. Seki, M. & Wood, R. D. DNA polymerase theta (POLQ) can extend from mismatches and from bases opposite a (6-4) photoproduct. DNA Repair 7, 119–127 (2008).

    CAS  PubMed  Google Scholar 

  72. 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  Google Scholar 

  73. Ahmad, A. et al. ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol. Cell Biol. 28, 5082–5092 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Arana, M. E., Seki, M., Wood, R. D., Rogozin, I. B. & Kunkel, T. A. Low-fidelity DNA synthesis by human DNA polymerase theta. Nucleic Acids Res. 36, 3847–3856 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Osia, B. et al. Cancer cells are uniquely susceptible to accumulation of MMBIR mutations. bioRxiv https://doi.org/10.1101/2020.07.19.209445 (2020).

    Article  Google Scholar 

  76. Layer, J. V. et al. Polymerase delta promotes chromosomal rearrangements and imprecise double-strand break repair. Proc. Natl Acad. Sci. USA 117, 27566–27577 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Meyer, D., Fu, B. X. & Heyer, W. D. DNA polymerases delta and lambda cooperate in repairing double-strand breaks by microhomology-mediated end-joining in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 112, E6907–E6916 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 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  Google Scholar 

  79. Mengwasser, K. E. et al. Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets. Mol. Cell 73, 885–899 e886 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Simsek, D. et al. DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLoS Genet. 7, e1002080 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Chen, X. et al. Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta, and IV reveal direct DNA sensing ability and differential physiological functions in DNA repair. DNA Repair 8, 961–968 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Della-Maria, J. et al. Human Mre11/human Rad50/Nbs1 and DNA ligase IIIalpha/XRCC1 protein complexes act together in an alternative nonhomologous end joining pathway. J. Biol. Chem. 286, 33845–33853 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang, H. et al. DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res. 65, 4020–4030 (2005).

    CAS  PubMed  Google Scholar 

  84. Boboila, C. et al. Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1). Proc. Natl Acad. Sci. USA 109, 2473–2478 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Masani, S., Han, L., Meek, K. & Yu, K. Redundant function of DNA ligase 1 and 3 in alternative end-joining during immunoglobulin class switch recombination. Proc. Natl Acad. Sci. USA 113, 1261–1266 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Harris, P. V. et al. Molecular cloning of Drosophila mus308, a gene involved in DNA cross-link repair with homology to prokaryotic DNA polymerase I genes. Mol. Cell Biol. 16, 5764–5771 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Muzzini, D. M., Plevani, P., Boulton, S. J., Cassata, G. & Marini, F. Caenorhabditis elegans POLQ-1 and HEL-308 function in two distinct DNA interstrand cross-link repair pathways. DNA Repair 7, 941–950 (2008).

    CAS  PubMed  Google Scholar 

  88. 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  Google Scholar 

  89. van Bostelen, I. & Tijsterman, M. Combined loss of three DNA damage response pathways renders C. elegans intolerant to light. DNA Repair 54, 55–62 (2017).

    PubMed  Google Scholar 

  90. Ira, G., Malkova, A., Liberi, G., Foiani, M. & Haber, J. E. Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast. Cell 115, 401–411 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Luo, G. et al. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat. Genet. 26, 424–429 (2000).

    CAS  PubMed  Google Scholar 

  92. Verma, P. & Greenberg, R. A. Noncanonical views of homology-directed DNA repair. Genes Dev. 30, 1138–1154 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. LaFave, M. C. & Sekelsky, J. Mitotic recombination: why? when? how? where? PLoS Genet. 5, e1000411 (2009).

    PubMed  PubMed Central  Google Scholar 

  94. LaRocque, J. R. et al. Interhomolog recombination and loss of heterozygosity in wild-type and Bloom syndrome helicase (BLM)-deficient mammalian cells. Proc. Natl Acad. Sci. USA 108, 11971–11976 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Wechsler, T., Newman, S. & West, S. C. Aberrant chromosome morphology in human cells defective for Holliday junction resolution. Nature 471, 642–646 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Carvajal-Garcia, J., Crown, K. N., Ramsden, D. A. & Sekelsky, J. DNA polymerase theta suppresses mitotic crossing over. PLoS Genet. 17, e1009267 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Davis, L., Khoo, K. J., Zhang, Y. & Maizels, N. POLQ suppresses interhomolog recombination and loss of heterozygosity at targeted DNA breaks. Proc. Natl Acad. Sci. USA 117, 22900–22909 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chandramouly, G. et al. Poltheta promotes the repair of 5’-DNA-protein crosslinks by microhomology-mediated end-joining. Cell Rep. 34, 108820 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Lemmens, B., van Schendel, R. & Tijsterman, M. Mutagenic consequences of a single G-quadruplex demonstrate mitotic inheritance of DNA replication fork barriers. Nat. Commun. 6, 8909 (2015).

    CAS  PubMed  Google Scholar 

  100. Yoon, J. H. et al. Error-prone replication through UV lesions by DNA polymerase theta protects against skin cancers. Cell 176, 1295–1309 e1215 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Roy, S. et al. p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLtheta pathways. Elife 7, e31723 (2018).

    PubMed  PubMed Central  Google Scholar 

  102. Deng, L. et al. Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements. Mol. Cell 73, 915–929 e916 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Leibowitz, M. L., Zhang, C. Z. & Pellman, D. Chromothripsis: a new mechanism for rapid karyotype evolution. Annu. Rev. Genet. 49, 183–211 (2015).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  105. Corneo, B. et al. Rag mutations reveal robust alternative end joining. Nature 449, 483–486 (2007).

    CAS  PubMed  Google Scholar 

  106. Cui, X. & Meek, K. Linking double-stranded DNA breaks to the recombination activating gene complex directs repair to the nonhomologous end-joining pathway. Proc. Natl Acad. Sci. USA 104, 17046–17051 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Li, Y., Gao, X. & Wang, J. Y. Comparison of two POLQ mutants reveals that a polymerase-inactive POLQ retains significant function in tolerance to etoposide and gamma-irradiation in mouse B cells. Genes. Cell 16, 973–983 (2011).

    CAS  Google Scholar 

  108. Martomo, S. A., Saribasak, H., Yokoi, M., Hanaoka, F. & Gearhart, P. J. Reevaluation of the role of DNA polymerase theta in somatic hypermutation of immunoglobulin genes. DNA Repair 7, 1603–1608 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bosma, G. C. et al. DNA-dependent protein kinase activity is not required for immunoglobulin class switching. J. Exp. Med. 196, 1483–1495 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Manis, J. P., Dudley, D., Kaylor, L. & Alt, F. W. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity 16, 607–617 (2002).

    CAS  PubMed  Google Scholar 

  111. 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  Google Scholar 

  112. Han, L. & Yu, K. Altered kinetics of nonhomologous end joining and class switch recombination in ligase IV-deficient B cells. J. Exp. Med. 205, 2745–2753 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kumar, R. J. et al. Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency. NAR. Cancer 2, zcaa038 (2020).

    PubMed  PubMed Central  Google Scholar 

  114. Panier, S. & Boulton, S. J. Double-strand break repair: 53BP1 comes into focus. Nat. Rev. Mol. Cell Biol. 15, 7–18 (2014).

    CAS  PubMed  Google Scholar 

  115. Isono, M. et al. BRCA1 directs the repair pathway to homologous recombination by promoting 53BP1 dephosphorylation. Cell Rep. 18, 520–532 (2017).

    CAS  PubMed  Google Scholar 

  116. 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  Google Scholar 

  117. 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  Google Scholar 

  118. Nacson, J. et al. BRCA1 mutation-specific responses to 53BP1 loss-induced homologous recombination and PARP inhibitor resistance. Cell Rep. 24, 3513–3527 e3517 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Setiaputra, D. & Durocher, D. Shieldin - the protector of DNA ends. EMBO Rep. 20, e47560 (2019).

    PubMed  PubMed Central  Google Scholar 

  120. Clouaire, T. et al. Comprehensive mapping of histone modifications at DNA double-strand breaks deciphers repair pathway chromatin signatures. Mol. Cell 72, 250–262 e256 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Schep, R. et al. Impact of chromatin context on Cas9-induced DNA double-strand break repair pathway balance. Mol. Cell 81, 2216–2230 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Liu, Q. et al. Subjugation of TGFbeta signaling by human papilloma virus in head and neck squamous cell carcinoma shifts DNA repair from homologous recombination to alternative end joining. Clin. Cancer Res. 24, 6001–6014 (2018).

    CAS  PubMed  Google Scholar 

  124. Liu, Q. et al. Loss of TGFbeta signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types. Sci. Transl. Med. 13, eabc4465 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Leeman, J. E. et al. Human papillomavirus 16 promotes microhomology-mediated end-joining. Proc. Natl Acad. Sci. USA 116, 21573–21579 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Knijnenburg, T. A. et al. Genomic and molecular landscape of DNA damage repair deficiency across the cancer genome atlas. Cell Rep. 23, 239–254 e236 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lemee, F. et al. DNA polymerase up-regulation is associated with poor survival in breast cancer perturbs DNA replication and promotes genetic instability. Proc. Natl Acad. Sci. USA 107, 13390–13395 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Higgins, G. S. et al. Overexpression of POLQ confers a poor prognosis in early breast cancer patients. Oncotarget 1, 175–184 (2010).

    PubMed  PubMed Central  Google Scholar 

  129. Allen, F. et al. Predicting the mutations generated by repair of Cas9-induced double-strand breaks. Nat. Biotechnol. 37, 64–72 (2019).

    CAS  Google Scholar 

  130. Ata, H. et al. Robust activation of microhomology-mediated end joining for precision gene editing applications. PLoS Genet. 14, e1007652 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. Chen, W. et al. Massively parallel profiling and predictive modeling of the outcomes of CRISPR/Cas9-mediated double-strand break repair. Nucleic Acids Res. 47, 7989–8003 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Mann, C. M. et al. The Gene Sculpt Suite: a set of tools for genome editing. Nucleic Acids Res. 47, W175–W182 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Shen, M. W. et al. Predictable and precise template-free CRISPR editing of pathogenic variants. Nature 563, 646–651 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. van Overbeek, M. et al. DNA repair profiling reveals nonrandom outcomes at cas9-mediated breaks. Mol. Cell 63, 633–646 (2016).

    PubMed  Google Scholar 

  135. Iyer, S. et al. Precise therapeutic gene correction by a simple nuclease-induced double-stranded break. Nature 568, 561–565 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).

    CAS  PubMed  Google Scholar 

  140. Riaz, N. et al. Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes. Nat. Commun. 8, 857 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. 22, 3764–3773 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).

    CAS  Google Scholar 

  143. Li, Y. et al. Patterns of somatic structural variation in human cancer genomes. Nature 578, 112–121 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Yang, L. et al. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153, 919–929 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Jones, R. E. et al. Escape from telomere-driven crisis is DNA ligase III dependent. Cell Rep. 8, 1063–1076 (2014).

    CAS  PubMed  Google Scholar 

  146. Nishizawa-Yokoi, A. et al. Agrobacterium T-DNA integration in somatic cells does not require the activity of DNA polymerase theta. New Phytol. 229, 2859–2872 (2021).

    CAS  PubMed  Google Scholar 

  147. Hu, Z. et al. Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat. Genet. 47, 158–163 (2015).

    CAS  PubMed  Google Scholar 

  148. Beagan, K. et al. Drosophila DNA polymerase theta utilizes both helicase-like and polymerase domains during microhomology-mediated end joining and interstrand crosslink repair. PLoS Genet. 13, e1006813 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. Higgins, G. S. et al. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res. 70, 2984–2993 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Russo, M. et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366, 1473–1480 (2019).

    CAS  PubMed  Google Scholar 

  151. Tobalina, L., Armenia, J., Irving, E., O’Connor, M. J. & Forment, J. V. A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance. Ann. Oncol. 32, 103–112 (2021).

    CAS  PubMed  Google Scholar 

  152. Waks, A. G. et al. Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer. Ann. Oncol. 31, 590–598 (2020).

    CAS  PubMed  Google Scholar 

  153. Weigelt, B. et al. Diverse BRCA1 and BRCA2 reversion mutations in circulating cell-free DNA of therapy-resistant breast or ovarian cancer. Clin. Cancer Res. 23, 6708–6720 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Ballhausen, A. et al. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nat. Commun. 11, 4740 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Litchfield, K. et al. Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Nat. Commun. 11, 3800 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).

    CAS  PubMed  Google Scholar 

  157. Pryor, J. M. et al. Essential role for polymerase specialization in cellular nonhomologous end joining. Proc. Natl Acad. Sci. USA 112, E4537–E4545 (2020).

    Google Scholar 

  158. Zhao, B., Rothenberg, E., Ramsden, D. A. & Lieber, M. R. The molecular basis and disease relevance of non-homologous DNA end joining. Nat. Rev. Mol. Cell Biol. 21, 765–781 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Lee, K. et al. Microhomology selection for microhomology mediated end joining in Saccharomyces cerevisiae. Genes 10, 284 (2019).

    CAS  PubMed Central  Google Scholar 

  160. Villarreal, D. D. et al. Microhomology directs diverse DNA break repair pathways and chromosomal translocations. PLoS Genet. 8, e1003026 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Decottignies, A. Microhomology-mediated end joining in fission yeast is repressed by pku70 and relies on genes involved in homologous recombination. Genetics 176, 1403–1415 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Kelso, A. A., Lopezcolorado, F. W., Bhargava, R. & Stark, J. M. Distinct roles of RAD52 and POLQ in chromosomal break repair and replication stress response. PLoS Genet. 15, e1008319 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Lee, K. & Lee, S. E. Saccharomyces cerevisiae Sae2- and Tel1-dependent single-strand DNA formation at DNA break promotes microhomology-mediated end joining. Genetics 176, 2003–2014 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Deshpande, R. A. et al. ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling. EMBO J. 33, 482–500 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Paull, T. T. & Gellert, M. A mechanistic basis for Mre11-directed DNA joining at microhomologies. Proc. Natl Acad. Sci. USA 97, 6409–6414 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 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  Google Scholar 

  167. Feldman, T. et al. Recurrent deletions in clonal hematopoiesis are driven by microhomology-mediated end joining. Nat. Commun. 12, 2455 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Sakofsky, C. J. & Malkova, A. Break induced replication in eukaryotes: mechanisms, functions, and consequences. Crit. Rev. Biochem. Mol. Biol. 52, 395–413 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhang, F. et al. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat. Genet. 41, 849–853 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Moon, A. F. et al. The X family portrait: structural insights into biological functions of X family polymerases. DNA Repair 6, 1709–1725 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Abkevich, V. et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br. J. Cancer 107, 1776–1782 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Birkbak, N. J. et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2, 366–375 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Popova, T. et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 72, 5454–5462 (2012).

    CAS  PubMed  Google Scholar 

  174. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).

    CAS  PubMed  Google Scholar 

  175. Chopra, N. et al. Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. Nat. Commun. 11, 2662 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Loibl, S. et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto. Ann. Oncol. 29, 2341–2347 (2018).

    CAS  PubMed  Google Scholar 

  177. Tutt, A. et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat. Med. 24, 628–637 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhao, E. Y. et al. Homologous recombination deficiency and platinum-based therapy outcomes in advanced breast cancer. Clin. Cancer Res. 23, 7521–7530 (2017).

    CAS  PubMed  Google Scholar 

  179. Tumiati, M. et al. A functional homologous recombination assay predicts primary chemotherapy response and long-term survival in ovarian cancer patients. Clin. Cancer Res. 24, 4482–4493 (2018).

    CAS  PubMed  Google Scholar 

  180. Ahrabi, S. et al. A role for human homologous recombination factors in suppressing microhomology-mediated end joining. Nucleic Acids Res. 44, 5743–5757 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by US NIH grants CA222092 and CA247773 to D.A.R. and G.P.G.

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Dale A. Ramsden & Gaorav P. Gupta

  2. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Dale A. Ramsden & Gaorav P. Gupta

  3. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Dale A. Ramsden, Juan Carvajal-Garcia & Gaorav P. Gupta

  4. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Gaorav P. Gupta

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The authors contributed equally to all aspects of the article.

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Correspondence to Dale A. Ramsden or Gaorav P. Gupta.

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Competing interests

G.P.G. receives research funding from Breakpoint Therapeutics, which is developing inhibitors of polymerase-θ. D.A.R. has a materials transfer agreement with Artios Pharma, and is using an Artios Pharma compound that inhibits polymerase-θ for research purposes, with no financial compensation.

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Glossary

A-family polymerases

One of seven groupings of eukaryotic DNA polymerases, consisting in mammals of polymerase-γ, polymerase-ν and polymerase-θ.

Presynaptic filament

In homologous recombination, resected DNA ends bound by RAD51; a precursor to synapsis of the ends with a sister chromatid or homologous chromosome.

Non-allelic HR

Recombination between homologous sequences that are not allelic (for example, between repeat sequences on different chromosomes).

G-quadruplex

Stable secondary structures of DNA generated by guanine-rich sequences; can impede DNA replication and transcription.

Genomic scar

A recurring pattern of mutagenesis that can be attributed to a specific cause or DNA repair process.

Mitotic DNA synthesis

DNA replication stress-induced repair process that involves DNA synthesis during mitosis, possibly involving break-induced replication.

Chromothripsis

Clustered chromosomal rearrangements observed in cancer that involve shattering of a chromosome (portion) into many fragments, most likely during erroneous mitotic progression, followed by mutagenic rejoining of the fragments.

Telomere crisis

A stage of telomere erosion that is sufficient to cause chromosome instability and cell death.

T-DNA

‘Transfer DNA’ that is transferred from the plasmid genome of some tumour-inducing bacteria into the genome of a plant host.

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Ramsden, D.A., Carvajal-Garcia, J. & Gupta, G.P. Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining. Nat Rev Mol Cell Biol 23, 125–140 (2022). https://doi.org/10.1038/s41580-021-00405-2

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