Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Double-strand break repair: 53BP1 comes into focus

Nature Reviews Molecular Cell Biology volume 15, pages 7–18 (2014)Cite this article

Subjects

Key Points

  • p53-binding protein 1 (53BP1) is a crucial component of DNA double-strand break (DSB) signalling and repair in mammalian cells.

  • It is recruited to DSBs downstream of RING finger 8 (RNF8)- and RNF168-dependent chromatin ubiquitylation. It reads a DSB-specific histone code that directly integrates ubiquitylation, methylation and acetylation signals at damaged chromatin.

  • Oligomerized 53BP1 binds directly to mono- and dimethylated Lys20 of histone 4 (H4K20me1 and H4K20me2) via its Tudor domain and to RNF168-ubiquitylated H2AK15 via its ubiquitylation-dependent recruitment (UDR) motif. The access of 53BP1 to mono- and dimethylated H4K20 and its recognition of ubiquitylated H2AK15 are modulated through several distinct mechanisms.

  • 53BP1 is a key regulator of DSB repair pathway choice. During G1, it promotes non-homologous end-joining (NHEJ)-mediated DSB repair by antagonizing long-range DNA end-resection, which is essential for DSB repair via homologous recombination.

  • PTIP (PAX transactivation activation domain-interacting protein) and RIF1 (RAP1-interacting factor 1) are 53BP1 effector proteins during DSB repair pathway choice. They bind to ataxia-telangiectasia mutated (ATM)-phosphorylated Ser/Thr-Gln (S/T-Q) sites in the 53BP1 amino terminus.

  • During S–G2, breast cancer 1 (BRCA1) and its interacting partner CtBP-interacting protein (CtIP) counteract 53BP1–RIF1 and 53BP1–PTIP complexes to promote DNA end-resection and thus homologous recombination-mediated DSB repair.

  • Mechanistically, how 53BP1 and its cofactors block resection in G1 and how these activities are counteracted by BRCA1 to enable DSB repair by homologous recombination in S phase remains an open question in the field.

Abstract

DNA double-strand break (DSB) signalling and repair is crucial to preserve genomic integrity and maintain cellular homeostasis. p53-binding protein 1 (53BP1) is an important regulator of the cellular response to DSBs that promotes the end-joining of distal DNA ends, which is induced during V(D)J and class switch recombination as well as during the fusion of deprotected telomeres. New insights have been gained into the mechanisms underlying the recruitment of 53BP1 to damaged chromatin and how 53BP1 promotes non-homologous end-joining-mediated DSB repair while preventing homologous recombination. From these studies, a model is emerging in which 53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with breast cancer 1 (BRCA1).

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: 53BP1 functions in the DNA damage response.
Figure 2: Domain structure and interaction partners of 53BP1.
Figure 3: The signal transduction pathway that leads to 53BP1 accumulation at damaged chromatin.
Figure 4: Model of 53BP1 recruitment to damaged chromatin.
Figure 5: Antagonistic relationship of 53BP1 and BRCA1 during DSB repair pathway choice.

Similar content being viewed by others

References

  1. Bennett, C. B., Lewis, A. L., Baldwin, K. K. & Resnick, M. A. Lethality induced by a single site-specific double-strand break in a dispensable yeast plasmid. Proc. Natl Acad. Sci. USA 90, 5613–5617 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Sandell, L. L. & Zakian, V. A. Loss of a yeast telomere: arrest, recovery, and chromosome loss. Cell 75, 729–739 (1993).

    CAS  PubMed  Google Scholar 

  3. 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 

  4. Iwabuchi, K., Bartel, P. L., Li, B., Marraccino, R. & Fields, S. Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl Acad. Sci. USA 91, 6098–6102 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Adams, M. M. & Carpenter, P. B. Tying the loose ends together in DNA double strand break repair with 53BP1. Cell Division 1, 19 (2006).

    PubMed  PubMed Central  Google Scholar 

  6. Harrison, J. C. & Haber, J. E. Surviving the breakup: the DNA damage checkpoint. Annu. Rev. Genet. 40, 209–235 (2006).

    CAS  PubMed  Google Scholar 

  7. Huen, M. S. Y. et al. Regulation of chromatin architecture by the PWWP domain-containing DNA damage-responsive factor EXPAND1/MUM1. Mol. Cell 37, 854–864 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Silverman, J., Takai, H., Buonomo, S. B. C., Eisenhaber, F. & de Lange, T. Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. Genes Dev. 18, 2108–2119 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Gong, Z., Cho, Y. W., Kim, J. E., Ge, K. & Chen, J. Accumulation of Pax2 transactivation domain interaction protein (PTIP) at sites of DNA breaks via RNF8-dependent pathway is required for cell survival after DNA damage. J. Biol. Chem. 284, 7284–7293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Jowsey, P. A., Doherty, A. J. & Rouse, J. Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation. J. Biol. Chem. 279, 55562–55569 (2004).

    CAS  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. Ditullio, R. A. et al. 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nature Cell Biol. 4, 998–1002 (2002).

    CAS  PubMed  Google Scholar 

  15. Fernandez-Capetillo, O. et al. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nature Cell Biol. 4, 993–997 (2002).

    CAS  PubMed  Google Scholar 

  16. Mochan, T. A., Venere, M., DiTullio, R. A. Jr & Halazonetis, T. D. 53BP1, an activator of ATM in response to DNA damage. DNA Repair 3, 945–952 (2004).

    CAS  PubMed  Google Scholar 

  17. Wang, B. 53BP1, a mediator of the DNA damage checkpoint. Science 298, 1435–1438 (2002).

    CAS  PubMed  Google Scholar 

  18. Ward, I. M., Minn, K., van Deursen, J. and Chen, J. p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Mol. Cell. Biol. 23, 2556–2563 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee, J. -H. & Paull, T. T. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 26, 7741–7748 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  21. Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010). References 20 and 21 show that 53BP1 is an inhibitor of DNA end-resection and homologous recombination.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. 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 

  24. 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 

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

    CAS  PubMed  Google Scholar 

  26. Dynan, W. S. & Yoo, S. Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res. 26, 1551–1559 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Difilippantonio, S. et al. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456, 529–533 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dimitrova, N., Chen, Y.-C. M., 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  Google Scholar 

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

    CAS  Google Scholar 

  31. Reina-San-Martin, B., Chen, J., Nussenzweig, A. & Nussenzweig, M. C. Enhanced intra-switch region recombination during immunoglobulin class switch recombination in 53BP1−/− B cells. Eur. J. Immunol. 37, 235–239 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Anderson, L., Henderson, C. & Adachi, Y. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol. Cell. Biol. 21, 1719–1729 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Rappold, I., Iwabuchi, K., Date, T. & Chen, J. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways. J. Cell Biol. 153, 613–620 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Schultz, L. B., Chehab, N. H., Malikzay, A. & Halazonetis, T. D. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J. Cell Biol. 151, 1381–1390 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. 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 

  38. Huen, M. S. Y. 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 

  39. 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 

  40. 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 

  41. 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). References 37 and 41 show that RNF168-mediated regulatory chromatin ubiquitylation is essential for the recruitment of 53BP1 to DSB sites.

    CAS  PubMed  Google Scholar 

  42. 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. 104, 20759–20763 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. 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 

  45. Goodarzi, A. A. & Jeggo, P. A. The repair and signaling responses to DNA double-strand breaks. Adv. Genet. 82, 1–45 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. 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 

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

    CAS  Google Scholar 

  50. Bekker-Jensen, S. et al. HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nature Cell Biol. 12, 80–86 (2009).

    PubMed  Google Scholar 

  51. 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 

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

    CAS  PubMed  Google Scholar 

  53. 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. 7, 16579–16587 (2013).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. 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. 106, 3166–3171 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 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 

  57. 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 

  58. Galanty, Y. et al. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462, 935–939 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 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 

  60. 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 

  61. 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 

  62. 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 

  63. Celeste, A. et al. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nature Cell Biol. 5, 675–679 (2003).

    CAS  PubMed  Google Scholar 

  64. Bekker-Jensen, S., Lukas, C., Melander, F., Bartek, J. & Lukas, J. Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. J. Cell Biol. 170, 201–211 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lou, Z., Minter-Dykhouse, K., Wu, X. & Chen, J. MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature 421, 957–961 (2003).

    CAS  PubMed  Google Scholar 

  66. Stewart, G. S., Wang, B., Bignell, C. R., Taylor, A. M. R. & Elledge, S. J. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421, 961–966 (2003).

    CAS  PubMed  Google Scholar 

  67. Joo, H. -Y. et al. Regulation of cell cycle progression and gene expression by H2A deubiquitination. Nature 449, 1068–1072 (2007).

    CAS  PubMed  Google Scholar 

  68. Morales, J. C. et al. Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability. J. Biol. Chem. 278, 14971–14977 (2003).

    CAS  PubMed  Google Scholar 

  69. Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013). Discovers that 53BP1 binds directly to RNF168-ubiquitylated H2A and that this binding is required for 53BP1 accumulation at damaged chromatin.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Botuyan, M. V. et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006). Reveals the molecular mechanism through which the 53BP1 Tudor domain binds to dimethylated H4K20.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Zgheib, O., Pataky, K., Brugger, J. & Halazonetis, T. D. An oligomerized 53BP1 tudor domain suffices for recognition of DNA double-strand breaks. Mol. Cell. Biol. 29, 1050–1058 (2009).

    CAS  PubMed  Google Scholar 

  72. Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).

    CAS  PubMed  Google Scholar 

  73. 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 

  74. Oda, H. et al. Regulation of the histone H4 monomethylase PR-Set7 by CRL4Cdt2-mediated PCNA-dependent degradation during DNA damage. Mol. Cell 40, 364–376 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Pei, H. et al. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470, 124–128 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Hajdu, I., Ciccia, A., Lewis, S. M. & Elledge, S. J. Wolf–Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage. Proc. Natl Acad. Sci. USA 108, 13130–13134 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Karachentsev, D., Sarma, K., Reinberg, D. & Steward, R. PR-Set7-dependent methylation of histone H4 Lys 20 functions in repression of gene expression and is essential for mitosis. Genes Dev. 19, 431–435 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Schotta, G. et al. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev. 22, 2048–2061 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Marango, J. et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 111, 3145–3154 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Nimura, K. et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf–Hirschhorn syndrome. Nature 460, 287–291 (2009).

    CAS  PubMed  Google Scholar 

  81. Hartlerode, A. J. et al. Impact of histone H4 lysine 20 methylation on 53BP1 responses to chromosomal double strand breaks. PLoS ONE 7, e49211 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  83. 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 

  84. Lee, J., Thompson, J. R., Botuyan, M. V. & Mer, G. Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A–tudor. Nature Struct. Mol. Biol. 15, 109–111 (2008).

    CAS  Google Scholar 

  85. Min, J. et al. L3MBTL1 recognition of mono- and dimethylated histones. Nature Struct. Mol. Biol. 14, 1229–1230 (2007).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  87. Smeenk, G. & van Attikum, H. The chromatin response to DNA breaks: leaving a mark on genome integrity. Annu. Rev. Biochem. 82, 55–80 (2013).

    CAS  PubMed  Google Scholar 

  88. Hsiao, K. Y. & Mizzen, C. A. Histone H4 deacetylation facilitates 53BP1 DNA damage signaling and double-strand break repair. J. Mol. Cell Biol. 5, 157–165 (2013).

    CAS  PubMed  Google Scholar 

  89. Tang, J. et al. Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nature Struct. Mol. Biol. 20, 317–325 (2013). References 88 and 89 showed that the acetylation status of H4K16 regulates the association of 53BP1 with dimethylated H4K20 during DSB repair.

    CAS  Google Scholar 

  90. Miller, K. M. et al. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nature Struct. Mol. Biol. 17, 1144–1151 (2010).

    CAS  Google Scholar 

  91. Lee, M. J., Lee, B. -H., Hanna, J., King, R. W. & Finley, D. Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes. Mol. Cell Proteomics 10, R110.003871–R110.003875 (2011).

    PubMed  Google Scholar 

  92. Sanders, S. L. et al. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 119, 603–614 (2004).

    CAS  PubMed  Google Scholar 

  93. 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 

  94. 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 

  95. Kilkenny, M. L. et al. Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair. Genes Dev. 22, 2034–2047 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Sanders, S. L., Arida, A. R. & Phan, F. P. Requirement for the phospho-H2AX binding module of Crb2 in double-strand break targeting and checkpoint activation. Mol. Cell. Biol. 30, 4722–4731 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Sofueva, S., Du, L.-L., Limbo, O., Williams, J. S. & Russell, P. BRCT domain interactions with phospho-histone H2A target Crb2 to chromatin at double-strand breaks and maintain the DNA damage checkpoint. Mol. Cell. Biol. 30, 4732–4743 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Du, L. L., Nakamura, T. M. & Russell, P. Histone modification-dependent and -independent pathways for recruitment of checkpoint protein Crb2 to double-strand breaks. Genes Dev. 20, 1583–1596 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Iwabuchi, K. et al. 53BP1 contributes to survival of cells irradiated with X-ray during G1 without Ku70 or Artemis. Genes Cells 11, 935–948 (2006).

    CAS  PubMed  Google Scholar 

  100. 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  Google Scholar 

  101. Bothmer, A. et al. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. Mol. Cell 42, 319–329 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Rai, R. et al. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J. 29, 2598–2610 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 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 

  104. 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 

  105. Zimmermann, M., Lottersberger, F., Buonomo, S. B., Sfeir, A. & de Lange, T. 53BP1 regulates repair using rif1 to control 5′ end resection. Science 399, 700–704 (2013).

    Google Scholar 

  106. Di Virgilio, M. et al. rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 399, 711–715 (2013).

    Google Scholar 

  107. Feng, L., Fong, K.-W., Wang, J., Wang, W. & Chen, J. RIF1 counteracts BRCA1-mediated end resection during DNA repair. J. Biol. Chem. 288, 11135–11143 (2013). References 103–107 identify RIF1 as a 53BP1 effector protein during DSB repair pathway choice.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Marcand, S., Wotton, D., Gilson, E. & Shore, D. Rap1p and telomere length regulation in yeast. Ciba Found. Symp. 211, 76–93; discussion 93–103 (1997).

    CAS  PubMed  Google Scholar 

  109. Wotton, D. & Shore, D. A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Genes Dev. 11, 748–760 (1997).

    CAS  PubMed  Google Scholar 

  110. Buonomo, S. B., Wu, Y., Ferguson, D. & de Lange, T. Mammalian Rif1 contributes to replication stress survival and homology-directed repair. J. Cell Biol. 187, 385–398 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Cornacchia, D. et al. Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J. 31, 3678–3690 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Yamazaki, S. et al. Rif1 regulates the replication timing domains on the human genome. EMBO J. 31, 3667–3677 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Xu, D. et al. Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication. EMBO J. 29, 3140–3155 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Rai, R. et al. The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection. Nature Struct. Mol. Biol. 18, 1400–1407 (2011).

    CAS  Google Scholar 

  115. Wang, X., Takenaka, K. & Takeda, S. PTIP promotes DNA double-strand break repair through homologous recombination. Genes Cells 15, 243–254 (2010).

    CAS  PubMed  Google Scholar 

  116. Shi, T. et al. Rif1 and Rif2 shape telomere function and architecture through multivalent Rap1 interactions. Cell 153, 1340–1353 (2013).

    CAS  PubMed  Google Scholar 

  117. 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  Google Scholar 

  118. Brzovic, P. S. et al. Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Proc. Natl Acad. Sci. USA 100, 5646–5651 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 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 

  121. 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  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose important findings could not be mentioned as primary literature and/or cited owing to space constraints. They thank D. Durocher for critically reading the manuscript. S.P. is supported by a European Molecular Biology Organization (EMBO) long-term fellowship. S.J.B. holds the Royal Society Wolfson Research Merit Award. Work in the laboratory of S.J.B. is funded by Cancer Research UK and by a European Research Council advanced investigator grant (RecMitMei).

Author information

Authors and Affiliations

  1. DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, London, EN6 3LD, South Mimms, UK

    Stephanie Panier & Simon J. Boulton

Authors
  1. Stephanie Panier
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Simon J. Boulton
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Simon J. Boulton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

DNA damage checkpoint

Signalling pathway that delays or arrests cell cycle progression in response to DNA damage.

Mediator

Acts downstream of the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases to recruit and/or activate additional DNA damage-responsive proteins.

Effector

Executes the functions of DNA damage response signalling, which include the activation of DNA damage checkpoints and DNA repair reactions.

Tudor domains

Protein–protein interaction domains that were first identified in the Drosophila melanogaster protein Tudor and bind to methylated Arg or Lys residues.

G2–M checkpoint

A type of DNA damage checkpoint that prevents cells with damaged genomes from entering into mitosis. It is predominantly mediated by the inhibition of CDC25 and cyclin-dependent kinase 1 (CDK1) by the effector kinases checkpoint kinase 1 (CHK1) and CHK2, and by p53.

V(D)J recombination

A type of programmed genome rearrangement in maturing T and B lymphocytes during which variable (V), diversity (D) and joining (J) immunoglobulin gene segments are randomly combined by induction of DNA double-strand breaks, and repaired by non-homologous end-joining to generate antibodies with different antigen specificities.

Class switch recombination

(CSR). Genome rearrangements in activated B lymphocytes that promote the generation of different antibody isotypes with the same antigen specificity. It involves the programmed formation and repair of DNA double-strand breaks within the switch regions between different antibody heavy chain gene segments.

E3 ubiquitin ligases

Key enzymes in the ubiquitylation reaction that is required for the attachment of ubiquitin moieties to a substrate protein. They provide substrate specificity to a multistep reaction that initially involves an E1 activating enzyme probably followed by E2 conjugating enzymes and then E3 ubiquitin ligases.

Valosin-containing protein

(VCP). AAA+ type ATPase that is important for the ATP-dependent unfolding of proteins and the disassembly of ubiquitylated protein–protein and protein–DNA complexes.

Lys48-linked polyubiquitin

Type of ubiquitin chain that targets proteins for degradation by the 26S proteasome.

Shelterin

Large multisubunit protein complex that caps chromosome ends and prevents illegitimate DNA repair reactions.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Panier, S., Boulton, S. Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol 15, 7–18 (2014). https://doi.org/10.1038/nrm3719

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3719

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing