Roles of histone ubiquitylation in DNA damage signaling

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

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): 1229–1240

[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): 359–370

[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, 1-12

[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): 1314–1323

[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): rs3

[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): 647–661

[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): 1361–1373

[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): 42462–42467

[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): 371–383

[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): 795–801

[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): 18475–18480

[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): 18475–18480

[13] Ciccia A, Elledge S J (2010). The DNA damage response: making it safe to play with knives. Mol Cell, 40(2): 179–204

[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): 435–446

[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): 935–939

[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): 7284–7293

[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): 473–485

[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): 592–603

[19] Huen M S, Chen J (2010). Assembly of checkpoint and repair machineries at DNA damage sites. Trends Biochem Sci, 35(2): 101–108

[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): 901–914

[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): 901–914

[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): 6104–6112

[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 double-strand breaks. Nature, 432(7015): 406–411

[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): 7028–7040

[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): 45–60

[26] Iwai K, Tokunaga F (2009). Linear polyubiquitination: a new regulator of NF-kappaB activation. EMBO Rep, 10(7): 706–713

[27] Jackson S P, Bartek J (2009). The DNA-damage response in human biology and disease. Nature, 461(7267): 1071–1078

[28] Kim H, Chen J, Yu X (2007). Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science, 316(5828): 1202–1205

[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): 1637–1640

[30] Komander D (2009). The emerging complexity of protein ubiquitination. Biochem Soc Trans, 37(Pt 5): 937–953

[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): 731–740

[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: 943–955

[33] Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J (2007). RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell, 131(5): 887–900

[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): 636–639

[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): 1160–1166

[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): 213–226

[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): 886–890

[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): 807–817

[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 ubiquitin-proteasome system as a regulator for DNA damage checkpoints. J Biol Chem, 282(24): 17330–17334

[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): 5312–5322

[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): 91–99

[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 damage-dependent ubiquitination by OTUB1. Nature, 466(7309): 941–946

[43] Panier S, Durocher D (2009). Regulatory ubiquitylation in response to DNA double-strand breaks. DNA Repair (Amst), 8(4): 436–443

[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): 886–895

[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): 572–582

[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): 2178–2188

[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): 3130–3139

[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): 5858–5868

[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): 2461–2468

[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): 970–981

[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): 3166–3171

[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): 775–783

[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): 741–749

[54] Smolka M B, Albuquerque C P, Chen S H, Zhou H (2007). Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases. Proc Natl Acad Sci USA, 104(25): 10364–10369

[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): 1198–1202

[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): 227–240

[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): 420–434

[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): 16910–16915

[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): 1213–1226

[60] Ulrich H, Walden H (2010). Ubiquitin signalling in DNA replication and repair. Nat Rev Mol Cell Biol, 11: 479–489

[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): 20759–20763

[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): 1194–1198

[63] Weake V M, Workman J L (2008). Histone ubiquitination: triggering gene activity. Mol Cell, 29(6): 653–663

[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): 18078–18084

[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): 11200–11205

[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): 31–43

[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): 663–675

Acknowledgments

This work was supported by Faculty Development Fund and Seed Funding for Applied Research to MSYH (No. 201007160001). SSD is supported in part by the URC-PDF Scheme and by Centre for Cancer Research HKU. The authors wish to thank Gabriel Lok for proof reading of the manuscript.

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