Advertisement

Frontiers in Biology

, 6:390 | Cite as

Roles of histone ubiquitylation in DNA damage signaling

  • Sui-Sui Dong
  • Michael S. Y. HuenEmail author
Review
First Online:
  • 63 Downloads

Abstract

Histone ubiquitylation has emerged as an important chromatin modification associated with DNA damage signaling and repair pathways. These histone marks, laid down by E3 ubiquitin ligases that include RNF8 and RNF168, decorate chromatin domains surrounding DNA double-strand breaks (DSBs). Recent work implicated ubiquitylated histones in orchestrating cell cycle checkpoints, DNA repair and gene transcription. Here we summarize recent advances that contribute to our current knowledge of the highly dynamic nature of DSB-associated histone ubiquitylation, and discuss major challenges ahead in understanding the versatility of ubiquitin conjugation in maintaining genome stability.

Keywords

DNA damage histone ubiquitylation ubiquitin ligase RNF8 RNF168 
This is a preview of subscription content, log in to check access.

References

  1. Al-Hakim A, Escribano-Diaz C, Landry M C, O’Donnell L, Panier S, Szilard R K, Durocher D (2010). The ubiquitous role of ubiquitin in the DNA damage response. DNA Repair (Amst), 9(12): 1229–1240CrossRefGoogle Scholar
  2. Bassing C H, Suh H, Ferguson D O, Chua K F, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt F W (2003). Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell, 114(3): 359–370PubMedCrossRefGoogle Scholar
  3. Bekker-Jensen S, Rendtlew Danielsen J, Fugger K, Gromova I, Nerstedt A, Lukas C, Bartek J, Lukas J, Mailand N (2010). HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nat Cell Biol, 12(1): 80–86, 1–12PubMedCrossRefGoogle Scholar
  4. Bennetzen M V, Larsen D H, Bunkenborg J, Bartek J, Lukas J, Andersen J S (2010). Site-specific phosphorylation dynamics of the nuclear proteome during the DNA damage response. Mol Cell Proteomics, 9(6): 1314–1323PubMedCrossRefGoogle Scholar
  5. Bensimon A, Schmidt A, Ziv Y, Elkon R, Wang S Y, Chen D J, Aebersold R, Shiloh Y (2010). ATM-dependent and -independent dynamics of the nuclear phosphoproteome after DNA damage. Sci Signal, 3(151): rs3PubMedCrossRefGoogle Scholar
  6. Bhaskara V, Dupré A, Lengsfeld B, Hopkins B B, Chan A, Lee J H, Zhang X, Gautier J, Zakian V, Paull T T (2007). Rad50 adenylate kinase activity regulates DNA tethering by Mre11/Rad50 complexes. Mol Cell, 25(5): 647–661PubMedCrossRefGoogle Scholar
  7. Botuyan M V, Lee J, Ward I M, Kim J E, Thompson J R, Chen J, Mer G (2006). Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell, 127(7): 1361–1373PubMedCrossRefGoogle Scholar
  8. Burma S, Chen B P, Murphy M, Kurimasa A, Chen D J (2001). ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem, 276(45): 42462–42467PubMedCrossRefGoogle Scholar
  9. Celeste A, Difilippantonio S, Difilippantonio M J, Fernandez-Capetillo O, Pilch D R, Sedelnikova O A, Eckhaus M, Ried T, Bonner W M, Nussenzweig A (2003). H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell, 114(3): 371–383PubMedCrossRefGoogle Scholar
  10. Chapman J R, Jackson S P (2008). Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. EMBO Rep, 9(8): 795–801PubMedCrossRefGoogle Scholar
  11. Chou D M, Adamson B, Dephoure N E, Tan X, Nottke A C, Hurov K E, Gygi S P, Colaiácovo M P, Elledge S J (2010a). A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc Natl Acad Sci USA, 107(43): 18475–18480PubMedCrossRefGoogle Scholar
  12. Chou D M, Adamson B, Dephoure N E, Tan X, Nottke A C, Hurov K E, Gygi S P, Colaiácovo M P, Elledge S J (2010b). A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc Natl Acad Sci USA, 107(43): 18475–18480PubMedCrossRefGoogle Scholar
  13. Ciccia A, Elledge S J (2010). The DNA damage response: making it safe to play with knives. Mol Cell, 40(2): 179–204PubMedCrossRefGoogle Scholar
  14. Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen D H, Pepperkok R, Ellenberg J, Panier S, Durocher D, Bartek J, Lukas J, Lukas C (2009). RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell, 136(3): 435–446PubMedCrossRefGoogle Scholar
  15. Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller K M, Jackson S P (2009). Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature, 462(7275): 935–939PubMedCrossRefGoogle Scholar
  16. Gong Z, Cho Y W, Kim J E, Ge K, Chen J (2009). 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(11): 7284–7293PubMedCrossRefGoogle Scholar
  17. Hopfner K P, Karcher A, Craig L, Woo T T, Carney J P, Tainer J A (2001). Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell, 105(4): 473–485PubMedCrossRefGoogle Scholar
  18. Huang J, Huen M S, Kim H, Leung C C, Glover J N, Yu X, Chen J (2009). RAD18 transmits DNA damage signalling to elicit homologous recombination repair. Nat Cell Biol, 11(5): 592–603PubMedCrossRefGoogle Scholar
  19. Huen M S, Chen J (2010). Assembly of checkpoint and repair machineries at DNA damage sites. Trends Biochem Sci, 35(2): 101–108PubMedCrossRefGoogle Scholar
  20. Huen M S, Grant R, Manke I, Minn K, Yu X, Yaffe M B, Chen J (2007a). RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell, 131(5): 901–914PubMedCrossRefGoogle Scholar
  21. Huen M S, Grant R, Manke I, Minn K, Yu X, Yaffe M B, Chen J (2007b). RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell, 131(5): 901–914PubMedCrossRefGoogle Scholar
  22. Huen M S, Huang J, Yuan J, Yamamoto M, Akira S, Ashley C, Xiao W, Chen J (2008). Noncanonical E2 variant-independent function of UBC13 in promoting checkpoint protein assembly. Mol Cell Biol, 28(19): 6104–6112PubMedCrossRefGoogle Scholar
  23. Huyen Y, Zgheib O, Ditullio R A Jr, Gorgoulis V G, Zacharatos P, Petty T J, Sheston E A, Mellert H S, Stavridi E S, Halazonetis T D (2004). Methylated lysine 79 of histone H3 targets 53BP1 to DNA doublestrand breaks. Nature, 432(7015): 406–411PubMedCrossRefGoogle Scholar
  24. Ikura T, Tashiro S, Kakino A, Shima H, Jacob N, Amunugama R, Yoder K, Izumi S, Kuraoka I, Tanaka K, Kimura H, Ikura M, Nishikubo S, Ito T, Muto A, Miyagawa K, Takeda S, Fishel R, Igarashi K, Kamiya K (2007). DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol Cell Biol, 27(20): 7028–7040PubMedCrossRefGoogle Scholar
  25. Ismail I H, Andrin C, McDonald D, Hendzel M J (2010). BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J Cell Biol, 191(1): 45–60PubMedCrossRefGoogle Scholar
  26. Iwai K, Tokunaga F (2009). Linear polyubiquitination: a new regulator of NF-kappaB activation. EMBO Rep, 10(7): 706–713PubMedCrossRefGoogle Scholar
  27. Jackson S P, Bartek J (2009). The DNA-damage response in human biology and disease. Nature, 461(7267): 1071–1078PubMedCrossRefGoogle Scholar
  28. Kim H, Chen J, Yu X (2007). Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science, 316(5828): 1202–1205PubMedCrossRefGoogle Scholar
  29. Kolas N K, Chapman J R, Nakada S, Ylanko J, Chahwan R, Sweeney F D, Panier S, Mendez M, Wildenhain J, Thomson T M, Pelletier L, Jackson S P, Durocher D (2007). Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science, 318(5856): 1637–1640PubMedCrossRefGoogle Scholar
  30. Komander D (2009). The emerging complexity of protein ubiquitination. Biochem Soc Trans, 37(Pt 5): 937–953PubMedCrossRefGoogle Scholar
  31. Larsen D H, Poinsignon C, Gudjonsson T, Dinant C, Payne M R, Hari F J, Danielsen J M, Menard P, Sand J C, Stucki M, Lukas C, Bartek J, Andersen J S, Lukas J (2010). The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage. J Cell Biol, 190(5): 731–740PubMedCrossRefGoogle Scholar
  32. Lilley C E, Chaurushiya M S, Boutell C, Landry S, Suh J, Panier S, Everett R D, Stewart G S, Durocher D, Weitzman M D (2010). A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses. EMBO J, 29: 943–955PubMedCrossRefGoogle Scholar
  33. Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J (2007). RNF8 ubiquitylates histones at DNA doublestrand breaks and promotes assembly of repair proteins. Cell, 131(5): 887–900PubMedCrossRefGoogle Scholar
  34. Manke I A, Lowery D M, Nguyen A, Yaffe M B (2003). BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science, 302(5645): 636–639PubMedCrossRefGoogle Scholar
  35. Matsuoka S, Ballif B A, Smogorzewska A, McDonald E R 3rd, Hurov K E, Luo J, Bakalarski C E, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi S P, Elledge S J (2007). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science, 316(5828): 1160–1166PubMedCrossRefGoogle Scholar
  36. Melander F, Bekker-Jensen S, Falck J, Bartek J, Mailand N, Lukas J (2008). Phosphorylation of SDT repeats in the MDC1 N terminus triggers retention of NBS1 at the DNA damage-modified chromatin. J Cell Biol, 181(2): 213–226PubMedCrossRefGoogle Scholar
  37. Morris J R, Boutell C, Keppler M, Densham R, Weekes D, Alamshah A, Butler L, Galanty Y, Pangon L, Kiuchi T, Ng T, Solomon E (2009). The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature, 462(7275): 886–890PubMedCrossRefGoogle Scholar
  38. Morris J R, Solomon E (2004). 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(8): 807–817PubMedCrossRefGoogle Scholar
  39. Mu J J, Wang Y, Luo H, Leng M, Zhang J, Yang T, Besusso D, Jung S Y, Qin J (2007). A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitinproteasome system as a regulator for DNA damage checkpoints. J Biol Chem, 282(24): 17330–17334PubMedCrossRefGoogle Scholar
  40. Munoz I M, Jowsey P A, Toth R, Rouse J (2007). Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. Nucleic Acids Res, 35(16): 5312–5322PubMedCrossRefGoogle Scholar
  41. Murr R, Loizou J I, Yang Y G, Cuenin C, Li H, Wang Z Q, Herceg Z (2006). Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat Cell Biol, 8(1): 91–99PubMedCrossRefGoogle Scholar
  42. Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang Y C, O’Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras A C, Natsume T, Suda T, Durocher D (2010). Non-canonical inhibition of DNA damagedependent ubiquitination by OTUB1. Nature, 466(7309): 941–946PubMedCrossRefGoogle Scholar
  43. Panier S, Durocher D (2009). Regulatory ubiquitylation in response to DNA double-strand breaks. DNA Repair (Amst), 8(4): 436–443CrossRefGoogle Scholar
  44. Paull T T, Rogakou E P, Yamazaki V, Kirchgessner C U, Gellert M, Bonner W M (2000). A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol, 10(15): 886–895PubMedCrossRefGoogle Scholar
  45. Plans V, Scheper J, Soler M, Loukili N, Okano Y, Thomson T M (2006). The RING finger protein RNF8 recruits UBC13 for lysine 63-based self polyubiquitylation. J Cell Biochem, 97(3): 572–582PubMedCrossRefGoogle Scholar
  46. Polanowska J, Martin J S, Garcia-Muse T, Petalcorin M I, Boulton S J (2006). A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. EMBO J, 25(10): 2178–2188PubMedCrossRefGoogle Scholar
  47. Polo S E, Kaidi A, Baskcomb L, Galanty Y, Jackson S P (2010). Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. EMBO J, 29(18): 3130–3139PubMedCrossRefGoogle Scholar
  48. Rogakou E P, Pilch D R, Orr A H, Ivanova V S, Bonner W M (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem, 273(10): 5858–5868PubMedCrossRefGoogle Scholar
  49. Sato Y, Yoshikawa A, Mimura H, Yamashita M, Yamagata A, Fukai S (2009). Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80. EMBO J, 28(16): 2461–2468PubMedCrossRefGoogle Scholar
  50. Shanbhag N M, Rafalska-Metcalf I U, Balane-Bolivar C, Janicki S M, Greenberg R A (2010). ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell, 141(6): 970–981PubMedCrossRefGoogle Scholar
  51. Shao G, Lilli D R, Patterson-Fortin J, Coleman K A, Morrissey D E, Greenberg R A (2009). The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci USA, 106(9): 3166–3171PubMedCrossRefGoogle Scholar
  52. Sims J J, Cohen R E (2009). Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80. Mol Cell, 33(6): 775–783PubMedCrossRefGoogle Scholar
  53. Smeenk G, Wiegant W W, Vrolijk H, Solari A P, Pastink A, van Attikum H (2010). The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage. J Cell Biol, 190(5): 741–749PubMedCrossRefGoogle Scholar
  54. Smolka M B, Albuquerque C P, Chen S H, Zhou H (2007). Proteomewide identification of in vivo targets of DNA damage checkpoint kinases. Proc Natl Acad Sci USA, 104(25): 10364–10369PubMedCrossRefGoogle Scholar
  55. Sobhian B, Shao G, Lilli D R, Culhane A C, Moreau L A, Xia B, Livingston D M, Greenberg R A (2007). RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science, 316(5828): 1198–1202PubMedCrossRefGoogle Scholar
  56. Spycher C, Miller E S, Townsend K, Pavic L, Morrice N A, Janscak P, Stewart G S, Stucki M (2008). Constitutive phosphorylation of MDC1 physically links the MRE11-RAD50-NBS1 complex to damaged chromatin. J Cell Biol, 181(2): 227–240PubMedCrossRefGoogle Scholar
  57. Stewart G S, Panier S, Townsend K, Al-Hakim A K, Kolas N K, Miller E S, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd P J, Stankovic T, Taylor A M, Durocher D (2009). The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell, 136(3): 420–434PubMedCrossRefGoogle Scholar
  58. Stewart G S, Stankovic T, Byrd P J, Wechsler T, Miller E S, Huissoon A, Drayson M T, West S C, Elledge S J, Taylor A M (2007). RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proc Natl Acad Sci USA, 104(43): 16910–16915PubMedCrossRefGoogle Scholar
  59. Stucki M, Clapperton J A, Mohammad D, Yaffe M B, Smerdon S J, Jackson S P (2005). MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell, 123(7): 1213–1226PubMedCrossRefGoogle Scholar
  60. Ulrich H, Walden H (2010). Ubiquitin signalling in DNA replication and repair. Nat Rev Mol Cell Biol, 11: 479–489PubMedCrossRefGoogle Scholar
  61. Wang B, Elledge S J (2007). Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci U S A, 104(52): 20759–20763PubMedCrossRefGoogle Scholar
  62. Wang B, Matsuoka S, Ballif B A, Zhang D, Smogorzewska A, Gygi S P, Elledge S J (2007). Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science, 316(5828): 1194–1198PubMedCrossRefGoogle Scholar
  63. Weake V M, Workman J L (2008). Histone ubiquitination: triggering gene activity. Mol Cell, 29(6): 653–663PubMedCrossRefGoogle Scholar
  64. Wu J, Prindle M J, Dressler G R, Yu X (2009). PTIP regulates 53BP1 and SMC1 at the DNA damage sites. J Biol Chem, 284(27): 18078–18084PubMedCrossRefGoogle Scholar
  65. Wu L, Luo K, Lou Z, Chen J (2008). MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks. Proc Natl Acad Sci USA, 105(32): 11200–11205PubMedCrossRefGoogle Scholar
  66. Xu Y, Sun Y, Jiang X, Ayrapetov M K, Moskwa P, Yang S, Weinstock D M, Price B D (2010). The p400 ATPase regulates nucleosome stability and chromatin ubiquitination during DNA repair. J Cell Biol, 191(1): 31–43PubMedCrossRefGoogle Scholar
  67. Zhao G Y, Sonoda E, Barber L J, Oka H, Murakawa Y, Yamada K, Ikura T, Wang X, Kobayashi M, Yamamoto K, Boulton S J, Takeda S (2007). A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. Mol Cell, 25(5): 663–675PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Genome Stability Research Laboratory, Department of Anatomy, Centre for Cancer ResearchUniversity of Hong KongHong KongChina

Personalised recommendations

Cite article

Buy options