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Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers

Key Points

  • Post-translational modification of proteins by ubiquitin and ubiquitin-like modifiers (UBLs) including SUMO have crucial and widespread roles in promoting cellular responses to DNA double-strand breaks (DSBs).

  • Cascades involving E1 activating enzymes, E2 conjugating enzymes and E3 ligases underlie the conjugation of ubiquitin and UBLs to cellular target proteins. These modifications are recognized and decoded by proteins containing ubiquitin- or UBL-binding domains, and are removed by ubiquitin- or UBL-specific proteases.

  • Chromatin ubiquitylation by RNF8, RNF168 and other E3 ubiquitin ligases gives rise to a complex ubiquitylation landscape at DSB sites that promotes accumulation of a range of important DNA repair factors near the lesions. Multiple regulatory mechanisms control and restrain the activity of these ubiquitin-mediated recruitment programmes.

  • Two major pathways for DSB repair, non-homologous end joining (NHEJ) and homologous recombination, are used by eukaryotic cells. Ubiquitin-dependent signalling processes have a key role in determining DSB repair pathway choice and functionality through the regulation of factors that control DSB end resection, as well as by modification of key NHEJ and homologous recombination components themselves.

  • A further level of complexity in DSB signalling pathways arises from the involvement of SUMO and other UBLs in promoting the functionality of these processes. Crosstalk between and co-regulation by ubiquitin and SUMO occurs at multiple levels within DSB repair responses.

  • Dysfunctions in ubiquitin signalling factors involved in DSB repair are tightly linked to severe disorders and syndromes resulting from genomic instability, demonstrating the physiological importance of these ubiquitin-dependent signalling responses. Mechanistic insights into how ubiquitin- and UBL-dependent processes promote DSB repair offer new therapeutic opportunities for diseases resulting from genomic instability.

Abstract

DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. The swift recognition and faithful repair of such damage is crucial for the maintenance of genomic stability, as well as for cell and organismal fitness. Signalling by ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs) orchestrates and regulates cellular responses to DSBs at multiple levels, often involving extensive crosstalk between these modifications. Recent findings have revealed compelling insights into the complex mechanisms by which ubiquitin and UBLs regulate protein interactions with DSB sites to promote accurate lesion repair and protection of genome integrity in mammalian cells. These advances offer new therapeutic opportunities for diseases linked to genetic instability.

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Figure 1: Principles of ubiquitin- and SUMO-dependent regulation in double-strand break (DSB) repair.
Figure 2: Ubiquitin-dependent protein assembly at double-strand break (DSB) sites by the RNF8–RNF168 pathway.
Figure 3: Ubiquitin-dependent regulation of double-strand break (DSB) repair pathway choice.
Figure 4: Ubiquitin–SUMO crosstalk in the RNF8–RNF168 pathway.

References

  1. 1

    Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001).

    CAS  PubMed  Google Scholar 

  4. 4

    Alt, F. W., Zhang, Y., Meng, F. L., Guo, C. & Schwer, B. Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell 152, 417–429 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    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  Google Scholar 

  6. 6

    Lieber, M. R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79, 181–211 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    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  Google Scholar 

  8. 8

    Chapman, J. R., Taylor, M. R. & Boulton, S. J. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell 47, 497–510 (2012).

    CAS  PubMed  Google Scholar 

  9. 9

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

    CAS  PubMed  Google Scholar 

  10. 10

    Bekker-Jensen, S. & Mailand, N. The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks. FEBS Lett. 585, 2914–2919 (2011).

    CAS  PubMed  Google Scholar 

  11. 11

    Kim, W. et al. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol. Cell 44, 325–340 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Wagner, S. A. et al. A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol. Cell. Proteomics 10, M111.013284 (2011).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012).

    CAS  PubMed  Google Scholar 

  14. 14

    Komander, D., Clague, M. J. & Urbe, S. Breaking the chains: structure and function of the deubiquitinases. Nat. Rev. Mol. Cell Biol. 10, 550–563 (2009).

    CAS  PubMed  Google Scholar 

  15. 15

    Nishi, R. et al. Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity. Nat. Cell Biol. 16, 1016–1026 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Schmidt, C. K. et al. Systematic E2 screening reveals a UBE2D–RNF138–CtIP axis promoting DNA repair. Nat. Cell Biol. 17, 1458–1470 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Elia, A. E. et al. Quantitative proteomic atlas of ubiquitination and acetylation in the DNA damage response. Mol. Cell 59, 867–881 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    van der Veen, A. G. & Ploegh, H. L. Ubiquitin-like proteins. Annu. Rev. Biochem. 81, 323–357 (2012).

    CAS  Google Scholar 

  19. 19

    Gareau, J. R. & Lima, C. D. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat. Rev. Mol. Cell Biol. 11, 861–871 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Hendriks, I. A. et al. Uncovering global SUMOylation signaling networks in a site-specific manner. Nat. Struct. Mol. Biol. 21, 927–936 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Huen, M. S. et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131, 901–914 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Morris, J. R. & Solomon, E. BRCA1: BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum. Mol. Genet. 13, 807–817 (2004).

    CAS  PubMed  Google Scholar 

  23. 23

    Gatti, M. et al. RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell Rep. 10, 226–238 (2015).

    CAS  PubMed  Google Scholar 

  24. 24

    Tatham, M. H. et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J. Biol. Chem. 276, 35368–35374 (2001).

    CAS  PubMed  Google Scholar 

  25. 25

    Dikic, I., Wakatsuki, S. & Walters, K. J. Ubiquitin-binding domains — from structures to functions. Nat. Rev. Mol. Cell Biol. 10, 659–671 (2009).

    CAS  PubMed  Google Scholar 

  26. 26

    Sims, J. J. & Cohen, R. E. Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of Rap80. Mol. Cell 33, 775–783 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Sato, Y. et al. Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80. EMBO J. 28, 2461–2468 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Panier, S. et al. Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks. Mol. Cell 47, 383–395 (2012).

    CAS  PubMed  Google Scholar 

  29. 29

    Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013). Reveals that 53BP1 contains a UDR domain that directly recognizes RNF168-ubiquitylated H2A and mediates its recruitment to DSBs.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Hecker, C. M., Rabiller, M., Haglund, K., Bayer, P. & Dikic, I. Specification of SUMO1- and SUMO2-interacting motifs. J. Biol. Chem. 281, 16117–16127 (2006).

    CAS  PubMed  Google Scholar 

  31. 31

    Bekker-Jensen, S. & Mailand, N. Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair 9, 1219–1228 (2010).

    CAS  PubMed  Google Scholar 

  32. 32

    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  Google Scholar 

  33. 33

    Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007).

    CAS  PubMed  Google Scholar 

  34. 34

    Kolas, N. K. et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318, 1637–1640 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    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  Google Scholar 

  36. 36

    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  PubMed  Google Scholar 

  37. 37

    Wang, B. & Elledge, S. J. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc. Natl Acad. Sci. USA 104, 20759–20763 (2007). References 21 and 33–37 show that RNF8 and RNF168 define a chromatin ubiquitylation pathway that is required for the accumulation of repair factors at DSB sites.

    CAS  PubMed  Google Scholar 

  38. 38

    Shanbhag, N. M., Rafalska-Metcalf, I. U., Balane-Bolivar, C., Janicki, S. M. & Greenberg, R. A. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell 141, 970–981 (2010).

    CAS  Article  Google Scholar 

  39. 39

    Stucki, M. et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123, 1213–1226 (2005).

    CAS  PubMed  Google Scholar 

  40. 40

    Mattiroli, F. et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 150, 1182–1195 (2012).

    CAS  PubMed  Google Scholar 

  41. 41

    Gatti, M. et al. A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase. Cell Cycle 11, 2538–2544 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Mattiroli, F., Uckelmann, M., Sahtoe, D. D., van Dijk, W. J. & Sixma, T. K. The nucleosome acidic patch plays a critical role in RNF168-dependent ubiquitination of histone H2A. Nat. Commun. 5, 3291 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Leung, J. W. et al. Nucleosome acidic patch promotes RNF168- and RING1B/BMI1-dependent H2AX and H2A ubiquitination and DNA damage signaling. PLoS Genet. 10, e1004178 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. 44

    Thorslund, T. et al. Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature 527, 389–393 (2015). Discovery that RNF8 promotes K63-linked ubiquitylation of H1-type histones to promote recruitment of RNF168.

    CAS  PubMed  Google Scholar 

  45. 45

    Bekker-Jensen, S. et al. HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nat. Cell Biol. 12, 80–86 (2010).

    CAS  PubMed  Google Scholar 

  46. 46

    Mailand, N., Gibbs-Seymour, I. & Bekker-Jensen, S. Regulation of PCNA–protein interactions for genome stability. Nat. Rev. Mol. Cell Biol. 14, 269–282 (2013).

    CAS  PubMed  Google Scholar 

  47. 47

    Raschle, M. et al. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links. Science 348, 1253671 (2015).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Huang, J. et al. RAD18 transmits DNA damage signalling to elicit homologous recombination repair. Nat. Cell Biol. 11, 592–603 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Poulsen, M., Lukas, C., Lukas, J., Bekker-Jensen, S. & Mailand, N. Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks. J. Cell Biol. 197, 189–199 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Chen, J., Feng, W., Jiang, J., Deng, Y. & Huen, M. S. Ring finger protein RNF169 antagonizes the ubiquitin-dependent signaling cascade at sites of DNA damage. J. Biol. Chem. 287, 27715–27722 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Polanowska, J., Martin, J. S., Garcia-Muse, T., Petalcorin, M. I. & Boulton, S. J. A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. EMBO J. 25, 2178–2188 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    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  Google Scholar 

  53. 53

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

    CAS  PubMed  Google Scholar 

  54. 54

    Ismail, I. H., Andrin, C., McDonald, D. & Hendzel, M. J. BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J. Cell Biol. 191, 45–60 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Ginjala, V. et al. BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair. Mol. Cell. Biol. 31, 1972–1982 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Pan, M. R., Peng, G., Hung, W. C. & Lin, S. Y. Monoubiquitination of H2AX protein regulates DNA damage response signaling. J. Biol. Chem. 286, 28599–28607 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Liu, C., Wu, J., Paudyal, S. C., You, Z. & Yu, X. CHFR is important for the first wave of ubiquitination at DNA damage sites. Nucleic Acids Res. 41, 1698–1710 (2013).

    CAS  PubMed  Google Scholar 

  58. 58

    Bekker-Jensen, S. et al. Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. J. Cell Biol. 173, 195–206 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Marechal, A. et al. PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Mol. Cell 53, 235–246 (2014).

    CAS  PubMed  Google Scholar 

  60. 60

    Elia, A. E. et al. RFWD3-dependent ubiquitination of RPA regulates repair at stalled replication forks. Mol. Cell 60, 280–293 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Ismail, I. H. et al. The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. Nat. Cell Biol. 17, 1446–1457 (2015).

    CAS  PubMed  Google Scholar 

  62. 62

    Panier, S. & Durocher, D. Push back to respond better: regulatory inhibition of the DNA double-strand break response. Nat. Rev. Mol. Cell Biol. 14, 661–672 (2013).

    CAS  PubMed  Google Scholar 

  63. 63

    Gudjonsson, T. et al. TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes. Cell 150, 697–709 (2012).

    CAS  PubMed  Google Scholar 

  64. 64

    Nicassio, F. et al. Human USP3 is a chromatin modifier required for S phase progression and genome stability. Curr. Biol. 17, 1972–1977 (2007).

    CAS  PubMed  Google Scholar 

  65. 65

    Mosbech, A., Lukas, C., Bekker-Jensen, S. & Mailand, N. The deubiquitylating enzyme USP44 counteracts the DNA double-strand break response mediated by the RNF8 and RNF168 ubiquitin ligases. J. Biol. Chem. 288, 16579–16587 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Sharma, N. et al. USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15. Cell Cycle 13, 106–114 (2014).

    CAS  PubMed  Google Scholar 

  67. 67

    Lancini, C. et al. Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells. J. Exp. Med. 211, 1759–1777 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Nakada, S. et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 466, 941–946 (2010).

    CAS  PubMed  Google Scholar 

  69. 69

    Juang, Y. C. et al. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function. Mol. Cell 45, 384–397 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Shao, G. et al. The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc. Natl Acad. Sci. USA 106, 3166–3171 (2009).

    CAS  PubMed  Google Scholar 

  71. 71

    Kato, K. et al. Fine-tuning of DNA damage-dependent ubiquitination by OTUB2 supports the DNA repair pathway choice. Mol. Cell 53, 617–630 (2014).

    CAS  PubMed  Google Scholar 

  72. 72

    Butler, L. R. et al. The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. EMBO J. 31, 3918–3934 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Meerang, M. et al. The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks. Nat. Cell Biol. 13, 1376–1382 (2011).

    CAS  PubMed  Google Scholar 

  74. 74

    Galanty, Y., Belotserkovskaya, R., Coates, J. & Jackson, S. P. RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev. 26, 1179–1195 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Acs, K. et al. The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks. Nat. Struct. Mol. Biol. 18, 1345–1350 (2011).

    CAS  PubMed  Google Scholar 

  76. 76

    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  Google Scholar 

  77. 77

    Orthwein, A. et al. Mitosis inhibits DNA double-strand break repair to guard against telomere fusions. Science 344, 189–193 (2014). Shows that the RNF8–RNF168-mediated DSB response is inactivated during mitosis to suppress telomere fusions and genomic instability.

    CAS  PubMed  Google Scholar 

  78. 78

    Peuscher, M. H. & Jacobs, J. J. DNA-damage response and repair activities at uncapped telomeres depend on RNF8. Nat. Cell Biol. 13, 1139–1145 (2011).

    CAS  PubMed  Google Scholar 

  79. 79

    Okamoto, K. et al. A two-step mechanism for TRF2-mediated chromosome-end protection. Nature 494, 502–505 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    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  Google Scholar 

  81. 81

    Lafranchi, L. et al. APC/CCdh1 controls CtIP stability during the cell cycle and in response to DNA damage. EMBO J. 33, 2860–2879 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Feng, L. & Chen, J. The E3 ligase RNF8 regulates KU80 removal and NHEJ repair. Nat. Struct. Mol. Biol. 19, 201–206 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Postow, L. & Funabiki, H. An SCF complex containing Fbxl12 mediates DNA damage-induced Ku80 ubiquitylation. Cell Cycle 12, 587–595 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Wijnhoven, P. et al. USP4 auto-deubiquitylation promotes homologous recombination. Mol. Cell 60, 362–373 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Liu, H. et al. The deubiquitylating enzyme USP4 cooperates with CtIP in DNA double-strand break end resection. Cell Rep. 13, 93–107 (2015).

    CAS  PubMed  Google Scholar 

  86. 86

    Sobhian, B. et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198–1202 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Kim, H., Chen, J. & Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202–1205 (2007).

    CAS  PubMed  Google Scholar 

  88. 88

    Wang, B. et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194–1198 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Wu, J. et al. Histone ubiquitination associates with BRCA1-dependent DNA damage response. Mol. Cell. Biol. 29, 849–860 (2009).

    CAS  PubMed  Google Scholar 

  90. 90

    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 

  91. 91

    Pesavento, J. J., Yang, H., Kelleher, N. L. & Mizzen, C. A. Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle. Mol. Cell. Biol. 28, 468–486 (2008).

    CAS  PubMed  Google Scholar 

  92. 92

    Mallette, F. A. et al. RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J. 31, 1865–1878 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    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  Google Scholar 

  94. 94

    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 

  95. 95

    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). References 94 and 95 demonstrate that 53BP1 inhibits DSB end resection and homologous recombination.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    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  Google Scholar 

  97. 97

    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  Google Scholar 

  98. 98

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

    CAS  PubMed  Google Scholar 

  99. 99

    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  Google Scholar 

  100. 100

    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  Google Scholar 

  101. 101

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

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Kakarougkas, A. et al. Co-operation of BRCA1 and POH1 relieves the barriers posed by 53BP1 and RAP80 to resection. Nucleic Acids Res. 41, 10298–10311 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    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  Google Scholar 

  104. 104

    Munoz, I. M., Jowsey, P. A., Toth, R. & Rouse, J. Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. Nucleic Acids Res. 35, 5312–5322 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

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

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Wang, J. et al. PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev. 28, 2693–2698 (2014).

    PubMed  PubMed Central  Google Scholar 

  107. 107

    Reczek, C. R., Szabolcs, M., Stark, J. M., Ludwig, T. & Baer, R. The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression. J. Cell Biol. 201, 693–707 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    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  Google Scholar 

  109. 109

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

    CAS  PubMed  Google Scholar 

  110. 110

    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  Google Scholar 

  111. 111

    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  Google Scholar 

  112. 112

    Shakya, R. et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334, 525–528 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Drost, R. et al. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell 20, 797–809 (2011).

    CAS  PubMed  Google Scholar 

  114. 114

    Yu, X., Fu, S., Lai, M., Baer, R. & Chen, J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 20, 1721–1726 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Kalb, R., Mallery, D. L., Larkin, C., Huang, J. T. & Hiom, K. BRCA1 is a histone-H2A-specific ubiquitin ligase. Cell Rep. 8, 999–1005 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Zhu, Q. et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 477, 179–184 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Wu-Baer, F., Lagrazon, K., Yuan, W. & Baer, R. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J. Biol. Chem. 278, 34743–34746 (2003).

    CAS  PubMed  Google Scholar 

  118. 118

    Orthwein, A. et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature 528, 422–426 (2015). Reveals that homologous recombination is suppressed in the G1 phase by CRL3KEAP1-mediated ubiquitylation of PALB2, preventing its binding to BRCA2.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Morris, J. R. et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 462, 886–890 (2009).

    CAS  PubMed  Google Scholar 

  120. 120

    Galanty, Y. et al. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462, 935–939 (2009). References 119 and 120 demonstrate that sumoylation at DSB sites promotes repair factor recruitment and activation.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Danielsen, J. R. et al. DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger. J. Cell Biol. 197, 179–187 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Yin, Y. et al. SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes Dev. 26, 1196–1208 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Luo, K., Zhang, H., Wang, L., Yuan, J. & Lou, Z. Sumoylation of MDC1 is important for proper DNA damage response. EMBO J. 31, 3008–3019 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Ismail, I. H. et al. CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage. Nucleic Acids Res. 40, 5497–5510 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Yan, J., Yang, X. P., Kim, Y. S., Joo, J. H. & Jetten, A. M. RAP80 interacts with the SUMO-conjugating enzyme UBC9 and is a novel target for sumoylation. Biochem. Biophys. Res. Commun. 362, 132–138 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Wu, N. et al. Scc1 sumoylation by Mms21 promotes sister chromatid recombination through counteracting Wapl. Genes Dev. 26, 1473–1485 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Jacome, A. et al. NSMCE2 suppresses cancer and aging in mice independently of its SUMO ligase activity. EMBO J. 34, 2604–2619 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Psakhye, I. & Jentsch, S. Protein group modification and synergy in the SUMO pathway as exemplified in DNA repair. Cell 151, 807–820 (2012). Describes the principle of SUMO group modification in DSB repair.

    CAS  PubMed  Google Scholar 

  129. 129

    Ouyang, K. J. et al. SUMO modification regulates BLM and RAD51 interaction at damaged replication forks. PLoS Biol. 7, e1000252 (2009).

    PubMed  PubMed Central  Google Scholar 

  130. 130

    Dou, H., Huang, C., Singh, M., Carpenter, P. B. & Yeh, E. T. Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex. Mol. Cell 39, 333–345 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Garvin, A. J. et al. The deSUMOylase SENP7 promotes chromatin relaxation for homologous recombination DNA repair. EMBO Rep. 14, 975–983 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Ivanov, A. V. et al. PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol. Cell 28, 823–837 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Goodarzi, A. A., Kurka, T. & Jeggo, P. A. KAP-1 phosphorylation regulates CHD3 nucleosome remodeling during the DNA double-strand break response. Nat. Struct. Mol. Biol. 18, 831–839 (2011).

    CAS  PubMed  Google Scholar 

  134. 134

    Noon, A. T. et al. 53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair. Nat. Cell Biol. 12, 177–184 (2010).

    CAS  PubMed  Google Scholar 

  135. 135

    Poulsen, S. L. et al. RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. J. Cell Biol. 201, 797–807 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Ma, T. et al. RNF111-dependent neddylation activates DNA damage-induced ubiquitination. Mol. Cell 49, 897–907 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Gibbs-Seymour, I. et al. Ubiquitin-SUMO circuitry controls activated Fanconi anemia ID complex dosage in response to DNA damage. Mol. Cell 57, 150–164 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Branigan, E., Plechanovova, A., Jaffray, E. G., Naismith, J. H. & Hay, R. T. Structural basis for the RING-catalyzed synthesis of K63-linked ubiquitin chains. Nat. Struct. Mol. Biol. 22, 597–602 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Tatham, M. H. et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat. Cell Biol. 10, 538–546 (2008).

    CAS  PubMed  Google Scholar 

  140. 140

    Guzzo, C. M. et al. RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. Sci. Signal. 5, ra88 (2012).

    PubMed  PubMed Central  Google Scholar 

  141. 141

    Hu, X., Paul, A. & Wang, B. Rap80 protein recruitment to DNA double-strand breaks requires binding to both small ubiquitin-like modifier (SUMO) and ubiquitin conjugates. J. Biol. Chem. 287, 25510–25519 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Li, T., Guan, J., Huang, Z., Hu, X. & Zheng, X. RNF168-mediated H2A neddylation antagonizes ubiquitylation of H2A and regulates DNA damage repair. J. Cell Sci. 127, 2238–2248 (2014).

    CAS  PubMed  Google Scholar 

  143. 143

    Hjerpe, R. et al. Changes in the ratio of free NEDD8 to ubiquitin triggers NEDDylation by ubiquitin enzymes. Biochem. J. 441, 927–936 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Hjerpe, R., Thomas, Y. & Kurz, T. NEDD8 overexpression results in neddylation of ubiquitin substrates by the ubiquitin pathway. J. Mol. Biol. 421, 27–29 (2012).

    CAS  PubMed  Google Scholar 

  145. 145

    Enchev, R. I., Schulman, B. A. & Peter, M. Protein neddylation: beyond cullin–RING ligases. Nat. Rev. Mol. Cell Biol. 16, 30–44 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Brown, J. S. et al. Neddylation promotes ubiquitylation and release of Ku from DNA-damage sites. Cell Rep. 11, 704–714 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Zhao, Y., Brickner, J. R., Majid, M. C. & Mosammaparast, N. Crosstalk between ubiquitin and other post-translational modifications on chromatin during double-strand break repair. Trends Cell Biol. 24, 426–434 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Xu, Y. et al. The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair. J. Cell Biol. 191, 31–43 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Maxwell, K. N. & Domchek, S. M. Cancer treatment according to BRCA1 and BRCA2 mutations. Nat. Rev. Clin. Oncol. 9, 520–528 (2012).

    CAS  PubMed  Google Scholar 

  150. 150

    Stewart, G. S. et al. RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proc. Natl Acad. Sci. USA 104, 16910–16915 (2007).

    CAS  PubMed  Google Scholar 

  151. 151

    Devgan, S. S. et al. Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Cell Death Differ. 18, 1500–1506 (2011). References 36 and 151 describe two independent cases of patients with biallelic mutations in RNF168 , providing direct evidence that ubiquitin-mediated recruitment of repair factors to DSB sites is crucial for human health.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Lilley, C. E. et al. A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses. EMBO J. 29, 943–955 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Chaurushiya, M. S. et al. Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain. Mol. Cell 46, 79–90 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Vyas, R. et al. RNF4 is required for DNA double-strand break repair in vivo. Cell Death Differ. 20, 490–502 (2013).

    CAS  PubMed  Google Scholar 

  155. 155

    Santos, M. A. et al. Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8. J. Exp. Med. 207, 973–981 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Li, L. et al. Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer. J. Exp. Med. 207, 983–997 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Bohgaki, T. et al. Genomic instability, defective spermatogenesis, immunodeficiency, and cancer in a mouse model of the RIDDLE syndrome. PLoS Genet. 7, e1001381 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Ward, I. M. et al. 53BP1 is required for class switch recombination. J. Cell Biol. 165, 459–464 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Manis, J. P. et al. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat. Immunol. 5, 481–487 (2004).

    CAS  PubMed  Google Scholar 

  160. 160

    Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    CAS  PubMed  Google Scholar 

  161. 161

    Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    CAS  PubMed  Google Scholar 

  162. 162

    Popovic, D., Vucic, D. & Dikic, I. Ubiquitination in disease pathogenesis and treatment. Nat. Med. 20, 1242–1253 (2014).

    CAS  PubMed  Google Scholar 

  163. 163

    Zhao, Y., Morgan, M. A. & Sun, Y. Targeting neddylation pathways to inactivate cullin-RING ligases for anticancer therapy. Antioxid. Redox Signal. 21, 2383–2400 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Magnaghi, P. et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat. Chem. Biol. 9, 548–556 (2013).

    CAS  PubMed  Google Scholar 

  165. 165

    Povlsen, L. K. et al. Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass. Nat. Cell Biol. 14, 1089–1098 (2012).

    CAS  PubMed  Google Scholar 

  166. 166

    Hendriks, I. A., Treffers, L. W., Verlaan- de Vries, M., Olsen, J. V. & Vertegaal, A. C. SUMO-2 orchestrates chromatin modifiers in response to DNA damage. Cell Rep. 10, 1778–1791 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Shalem, O. et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014).

    CAS  PubMed  Google Scholar 

  170. 170

    Wang, T., Wei, J. J., Sabatini, D. M. & Lander, E. S. Genetic screens in human cells using the CRISPR-Cas9 system. Science 343, 80–84 (2014).

    CAS  PubMed  Google Scholar 

  171. 171

    Hospenthal, M. K., Mevissen, T. E. & Komander, D. Deubiquitinase-based analysis of ubiquitin chain architecture using Ubiquitin Chain Restriction (UbiCRest). Nat. Protoc. 10, 349–361 (2015).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors apologize to all researchers whose important findings could not be cited owing to page limitations, and thank Jiri Lukas (The Novo Nordisk Foundation Center for Protein Research) for critical reading of the manuscript. Work in the authors' laboratory is funded by grants from The Novo Nordisk Foundation (Grant no. NNF14CC0001), The European Research Council, The Danish Council for Independent Research, The Lundbeck Foundation and The Danish Cancer Society.

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PowerPoint slides

Glossary

Writers, readers and erasers

Factors that lay down (writers), recognize (readers) and remove (erasers) specific post-translational modifications of proteins.

Atypical polyubiquitin chains

Low-abundant ubiquitin chain types, including K6, K27, K29 and K33 linkages, whose cellular functions are not yet well understood.

RING-type E3 ligases

A family of E3 ubiquitin ligases containing the RING (really interesting new gene) domain, more than 600 of which are encoded in the human genome, and which mediate direct transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to the substrate protein.

HECT-type E3 ligase

A type of E3 ubiquitin ligase, approximately 30 of which are present in mammals, harbouring a carboxy-terminal HECT (homologous to the E6-AP C terminus) domain that accepts ubiquitin from an E2 enzyme through formation of a thioester intermediate and subsequently transfers the ubiquitin moiety to a protein substrate.

Translesion DNA synthesis

A DNA damage tolerance pathway involving specialized, low-fidelity DNA polymerases that allow replication past DNA lesions, albeit in a potentially error-prone manner that contributes to DNA damage-induced mutagenesis.

OTU family

A subfamily of cysteine protease DUBs that contain an ovarian tumour (OTU) domain.

Ubiquitin-selective segregase p97

A highly abundant AAA+ ATPase (also known as VCP (valosin-containing protein)) that remodels ubiquitylated client proteins and complexes and has a widespread involvement in ubiquitin-mediated cellular processes.

Immunoglobulin class-switch recombination

(CSR). The process in activated B lymphocytes that promotes the generation of different antibody isotypes with the same antigen specificity by switching antibody heavy-chain gene segments, initiated by programmed DSBs.

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Schwertman, P., Bekker-Jensen, S. & Mailand, N. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nat Rev Mol Cell Biol 17, 379–394 (2016). https://doi.org/10.1038/nrm.2016.58

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