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DNA damage emergency: cellular garbage disposal to the rescue?

Oncogene volume 33, pages 805–813 (2014)Cite this article

Subjects

Abstract

The proteasome is a cellular machine found in the cytosol, nucleus and on chromatin that performs much of the proteolysis in eukaryotic cells. Recent reports show it is enriched at sites of double-stranded DNA breaks (DSBs) in mammalian cells. What is it doing there? This review will address three possibilities suggested by recent reports: in degrading proteins after their ubiquitination at and eviction from chromatin; as a deubiquitinase, specific to the antagonism of ubiquitin conjugates generated as part of the signalling of a DSB; and as a functional component of DNA repair mechanism itself. These findings add complexity to the proteasome as a potential therapeutic target in cancer treatment.

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Abbreviations

53BP1:

p53-binding protein 1

BRCA1:

breast cancer susceptibility gene 1

BRCA2:

breast cancer susceptibility gene 2

BRCC36:

BRCA1/BRCA2-containing complex, subunit 3

DDR:

DNA damage response

DSB:

double-strand break

DSS1:

deleted in split-hand/split-foot 1

DUB:

deubiquitinating enzyme

HR:

homologous recombination

IR:

ionising radiation

JAMM:

Jab1/MPN domain metalloenzyme

JMJD2:

Jumonji domain 2

MDC1:

mediator of DNA damage protein 1

Mono-Ub:

mono-ubiquitin

NHEJ:

non-homologous end joining

OTUB1:

OTU domain, ubiquitin aldehyde-binding 1

Poly-Ub:

poly-ubiquitin

POH1:

pad one homologue-1

PSMA:

proteasome (prosome, macropain) subunit, alpha type

PSMD:

proteasome (prosome, macropain) 26S subunit, non-ATPase

RAD18:

radiation-sensitive 18

RAD51:

RAD51 homologue C (S. Cerevisiae)

RAP80:

receptor-associated protein 80

RNF:

ring finger protein

RPA:

replication protein A

Rpn:

regulatory particle non-ATPase

ssDNA:

single-stranded DNA

SUMO:

small ubiquitin-like modifier

TRIP12:

thyroid hormone interactor 12

Ub:

ubiquitin

UBC:

Ub-conjugating enzyme

UBR5:

ubiquitin protein ligase E3 component n-recognin 5

USP:

ubiquitin-specific protease

VCP:

valosin containing protein

References

  1. Hochstrasser M . Evolution and function of ubiquitin-like protein-conjugation systems. Nat Cell Biol 2000; 2: E153–E157.

    CAS  PubMed  Google Scholar 

  2. Wang C, Xi J, Begley TP, Nicholson LK . Solution structure of ThiS and implications for the evolutionary roots of ubiquitin. Nat Struct Mol Biol 2001; 8: 47–51.

    Google Scholar 

  3. Goldstein G, Scheid M, Hammerling U, Boyse EA, Schlesinger DH, Niall HD . Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc Natl Acad Sci USA 1975; 72: 11–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Hicke L . Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol 2001; 2: 195–201.

    CAS  PubMed  Google Scholar 

  5. Ciechanover A, Heller H, Katzetzion R, Hershko A . Activation of the heat-stable polypeptide of the ATP-dependent proteolytic system. Proc Natl Acad Sci USA Biol Sci 1981; 78: 761–765.

    CAS  Google Scholar 

  6. Hershko A, Heller H, Elias S, Ciechanover A . Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 1983; 258: 8206–8214.

    CAS  PubMed  Google Scholar 

  7. Amerik AY, Hochstrasser M . Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 2004; 1695: 189–207.

    CAS  PubMed  Google Scholar 

  8. Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J 2006; 25: 4877–4887.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Goldknopf IL, Busch H . Isopeptide linkage between nonhistone and histone-2A polypeptides of chromosomal conjugate-proteins-A24. Proc Natl Acad Sci USA 1977; 74: 864–868.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Peng JM, Schwartz D, Elias JE, Thoreen CC, Cheng DM, Marsischky G et al. A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 2003; 21: 921–926.

    CAS  PubMed  Google Scholar 

  11. Varadan R, Walker O, Pickart C, Fushman D . Structural properties of polyubiquitin chains in solution. J Mol Biol 2002; 324: 637–647.

    CAS  PubMed  Google Scholar 

  12. Fushman D, Walker O . Exploring the linkage dependence of polyubiquitin conformations using molecular modeling. J Mol Biol 2010; 395: 803–814.

    CAS  PubMed  Google Scholar 

  13. Kim HT, Kim KP, Lledias F, Kisselev AF, Scaglione KM, Skowyra D et al. Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages. J Biol Chem 2007; 282: 17375–17386.

    CAS  PubMed  Google Scholar 

  14. Sowa ME, Bennett EJ, Gygi SP, Harper JW . Defining the human deubiquitinating enzyme interaction landscape. Cell 2009; 138: 389–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Komander D, Clague MJ, Urbe S . Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 2009; 10: 550–563.

    CAS  PubMed  Google Scholar 

  16. Jacobson AD, Zhang NY, Xu P, Han KJ, Noone S, Peng J et al. The lysine 48 and lysine 63 ubiquitin conjugates are processed differently by the 26 s proteasome. J Biol Chem 2009; 284: 35485–35494.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Peth A, Besche HC, Goldberg AL . Ubiquitinated proteins activate the proteasome by binding to Usp14/Ubp6, which causes 20S gate opening. Mol Cell 2009; 36: 794–804.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Peth A, Uchiki T, Goldberg AL . ATP-dependent steps in the binding of ubiquitin conjugates to the 26S proteasome that commit to degradation. Mol Cell 2010; 40: 671–681.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Johnson ES, Ma PCM, Ota IM, Varshavsky A . A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem 1995; 270: 17442–17456.

    CAS  PubMed  Google Scholar 

  20. Matilla A, Gorbea C, Einum DD, Townsend J, Michalik A, van Broeckhoven C et al. Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex. Hum Mol Genet 2001; 10: 2821–2831.

    CAS  PubMed  Google Scholar 

  21. Cooper EM, Cutcliffe C, Kristiansen TZ, Pandey A, Pickart CM, Cohen RE . K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J 2009; 28: 621–631.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Xu P, Duong DM, Seyfried NT, Cheng DM, Xie Y, Robert J et al. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 2009; 137: 133–145.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Virdee S, Ye Y, Nguyen DP, Komander D, Chin JW . Engineered diubiquitin synthesis reveals Lys29-isopeptide specificity of an OTU deubiquitinase. Nat Chem Biol 2010; 6: 750–757.

    CAS  PubMed  Google Scholar 

  24. Nishikawa H, Ooka S, Sato K, Arima K, Okamoto J, Klevit RE et al. Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase. J Biol Chem 2003; 279: 3916–3924.

    PubMed  Google Scholar 

  25. Ben-Saadon R, Zaaroor D, Ziv T, Ciechanover A . The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity. Mol Cell 2006; 24: 701–711.

    CAS  PubMed  Google Scholar 

  26. Patterson-Fortin J, Shao G, Bretscher H, Messick TE, Greenberg RA . Differential regulation of JAMM domain deubiquitinating enzyme activity within the RAP80 complex. J Biol Chem 2010; 285: 30971–30981.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ . MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 2003; 421: 961–966.

    CAS  PubMed  Google Scholar 

  28. Mochan TA, Venere M, DiTullio RA, Halazonetis TD . 53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage. Cancer Res 2003; 63: 8586–8591.

    CAS  PubMed  Google Scholar 

  29. Lou Z, Chini CC, Minter-Dykhouse K, Chen J . Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. J Biol Chem 2003; 278: 13599–13602.

    CAS  PubMed  Google Scholar 

  30. Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 2007; 131: 901–914.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 2007; 318: 1637–1640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 2007; 131: 887–900.

    CAS  PubMed  Google Scholar 

  33. Wang B, Elledge SJ . Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci USA 2007; 104: 20759–20763.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen DH, Pepperkok R et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 2009; 136: 435–446.

    CAS  PubMed  Google Scholar 

  35. Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 2009; 136: 420–434.

    CAS  PubMed  Google Scholar 

  36. Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 2007; 316: 1194–1198.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Huang J, Huen MS, Kim H, Leung CC, Glover JN, Yu X et al. RAD18 transmits DNA damage signalling to elicit homologous recombination repair. Nat Cell Biol 2009; 11: 592–603.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Marteijn JA, Bekker-Jensen S, Mailand N, Lans H, Schwertman P, Gourdin AM et al. Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. J Cell Biol 2009; 186: 835–847.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Mallette FA, Mattiroli F, Cui G, Young LC, Hendzel MJ, Mer G et al. RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J 2012; 31: 1865–1878.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Butler LR, Densham RM, Jia J, Garvin AJ, Stone HR, Shah V et al. The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. EMBO J 2012; 31: 3918–3934.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Mattiroli F, Vissers JH, van Dijk WJ, Ikpa P, Citterio E, Vermeulen W et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 2012; 150: 1182–1195.

    CAS  PubMed  Google Scholar 

  42. Yan J, Jetten AM . RAP80 and RNF8, key players in the recruitment of repair proteins to DNA damage sites. Cancer Lett 2008; 271: 179–190.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu J, Liu C, Chen J, Yu X . Rap80 is important for genomic stability and is required for stabilizing the BRCA1-A complex at DNA damage sites in vivo. J Biol Chem 2012; 287: 22919–22926.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sobhian B, Shao G, Lilli DR, Culhane AC, Moreau LA, Xia B et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 2007; 316: 1198–1202.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Nakada S, Yonamine RM, Matsuo K . RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1. Cancer Res 2012; 72: 4974–4983.

    CAS  PubMed  Google Scholar 

  46. Mott C, Symington LS . RAD51-independent inverted-repeat recombination by a strand-annealing mechanism. DNA Repair 2011; 10: 408–415.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sigurdsson S, Van Komen S, Bussen W, Schild D, Albala JS, Sung P . Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange. Genes Develop 2001; 15: 3308–3318.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Dou H, Huang C, Singh M, Carpenter PB, Yeh ET . Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex. Mol Cell 2010; 39: 333–345.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Galanty Y, Belotserkovskaya R, Coates J, Jackson SP . RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Develop 2012; 26: 1179–1195.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yin Y, Seifert A, Chua JS, Maure JF, Golebiowski F, Hay RT . SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes Develop 2012; 26: 1196–1208.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Vyas R, Kumar R, Clermont F, Helfricht A, Kalev P, Sotiropoulou P et al. RNF4 is required for DNA double-strand break repair in vivo. Cell Death Differ 2012; 20: 490–502.

    PubMed  PubMed Central  Google Scholar 

  53. Zhang D, Zaugg K, Mak TW, Elledge SJ . A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response. Cell 2006; 126: 529–542.

    CAS  PubMed  Google Scholar 

  54. Popov N, Herold S, Llamazares M, Schulein C, Eilers M . Fbw7 and Usp28 regulate Myc protein stability in response to DNA damage. Cell Cycle 2007; 6: 2327–2331.

    CAS  PubMed  Google Scholar 

  55. Nicassio F, Corrado N, Vissers JH, Areces LB, Bergink S, Marteijn JA et al. Human USP3 is a chromatin modifier required for S phase progression and genome stability. Curr Biol 2007; 17: 1972–1977.

    CAS  PubMed  Google Scholar 

  56. Joo HY, Zhai L, Yang C, Nie S, Erdjument-Bromage H, Tempst P et al. Regulation of cell cycle progression and gene expression by H2A deubiquitination. Nature 2007; 449: 1068–1072.

    CAS  PubMed  Google Scholar 

  57. Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 2010; 466: 941–946.

    CAS  PubMed  Google Scholar 

  58. Wiener R, Zhang X, Wang T, Wolberger C . The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature 2012; 483: 618–622.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Juang YC, Landry MC, Sanches M, Vittal V, Leung CC, Ceccarelli DF et al. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function. Mol Cell 2012; 45: 384–397.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sato Y, Yamagata A, Goto-Ito S, Kubota K, Miyamoto R, Nakada S et al. Molecular basis of Lys-63-linked polyubiquitination inhibition by the interaction between human deubiquitinating enzyme OTUB1 and ubiquitin-conjugating enzyme UBC13. J Biol Chem 2012; 287: 25860–25868.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Feng L, Wang J, Chen J . The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments. J Biol Chem 2010; 285: 30982–30988.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA . The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci USA 2009; 106: 3166–3171.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Acs K, Luijsterburg MS, Ackermann L, Salomons FA, Hoppe T, Dantuma NP . The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks. Nat Struct Mol Biol 2011; 18: 1345–1350.

    CAS  PubMed  Google Scholar 

  64. Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N et al. The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks. Nat Cell Biol 2011; 13: 1376–1382.

    CAS  PubMed  Google Scholar 

  65. Dantuma NP, Groothuis TA, Salomons FA, Neefjes J . A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling. J Cell Biol 2006; 173: 19–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Shi W, Ma Z, Willers H, Akhtar K, Scott SP, Zhang J et al. Disassembly of MDC1 foci is controlled by ubiquitin-proteasome-dependent degradation. J Biol Chem 2008; 283: 31608–31616.

    CAS  PubMed  Google Scholar 

  67. Murakawa Y, Sonoda E, Barber LJ, Zeng W, Yokomori K, Kimura H et al. Inhibitors of the proteasome suppress homologous DNA recombination in mammalian cells. Cancer Res 2007; 67: 8536–8543.

    CAS  PubMed  Google Scholar 

  68. Jacquemont C, Taniguchi T . Proteasome function is required for DNA damage response and fanconi anemia pathway activation. Cancer Res 2007; 67: 7395–7405.

    CAS  PubMed  Google Scholar 

  69. Gudmundsdottir K, Lord CJ, Ashworth A . The proteasome is involved in determining differential utilization of double-strand break repair pathways. Oncogene 2007; 26: 7601–7606.

    CAS  PubMed  Google Scholar 

  70. Ben-Aroya S, Agmon N, Yuen K, Kwok T, McManus K, Kupiec M et al. Proteasome nuclear activity affects chromosome stability by controlling the turnover of Mms22, a protein important for DNA repair. PLoS Genet 2010; 6: e1000852.

    PubMed  PubMed Central  Google Scholar 

  71. Liu H, Buus R, Clague MJ, Urbe S . Regulation of ErbB2 receptor status by the proteasomal DUB POH1. PLoS ONE 2009; 4: e5544.

    PubMed  PubMed Central  Google Scholar 

  72. Hanna J, Leggett DS, Finley D . Ubiquitin depletion as a key mediator of toxicity by translational inhibitors. Mol Cell Biol 2003; 23: 9251–9261.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Postow L, Ghenoiu C, Woo EM, Krutchinsky AN, Chait BT, Funabiki H . Ku80 removal from DNA through double strand break-induced ubiquitylation. J Cell Biol 2008; 182: 467–479.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Krogan NJ, Lam MH, Fillingham J, Keogh MC, Gebbia M, Li J et al. Proteasome involvement in the repair of DNA double-strand breaks. Mol Cell 2004; 16: 1027–1034.

    CAS  PubMed  Google Scholar 

  75. Kuehn L, Dahlmann B . Structural and functional properties of proteasome activator PA28. Mol Biol Rep 1997; 24: 89–93.

    CAS  PubMed  Google Scholar 

  76. Ustrell V, Hoffman L, Pratt G, Rechsteiner M . PA200, a nuclear proteasome activator involved in DNA repair. EMBO J 2002; 21: 3516–3525.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Blickwedehl J, Agarwal M, Seong C, Pandita RK, Melendy T, Sung P et al. Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability. Proc Natl Acad Sci USA 2008; 105: 16165–16170.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Blickwedehl J, McEvoy S, Wong I, Kousis P, Clements J, Elliott R et al. Proteasomes and proteasome activator 200 kDa (PA200) accumulate on chromatin in response to ionizing radiation. Radiat Res 2007; 167: 663–674.

    CAS  PubMed  Google Scholar 

  79. Levy-Barda A, Lerenthal Y, Davis AJ, Chung YM, Essers J, Shao Z et al. Involvement of the nuclear proteasome activator PA28gamma in the cellular response to DNA double-strand breaks. Cell Cycle 2011; 10: 24.

    Google Scholar 

  80. Kim HT, Goldberg AL . S5a/Rpn10, a UIM-protein, as a universal substrate for ubiquitination. Methods Mol Biol 2012; 832: 653–660.

    CAS  PubMed  Google Scholar 

  81. Kim HT, Kim KP, Uchiki T, Gygi SP, Goldberg AL . S5a promotes protein degradation by blocking synthesis of nondegradable forked ubiquitin chains. EMBO J 2009; 28: 1867–1877.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Raman M, Havens CG, Walter JC, Harper JW . A genome-wide screen identifies p97 as an essential regulator of DNA damage-dependent CDT1 destruction. Mol Cell 2011; 44: 72–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Franz A, Orth M, Pirson PA, Sonneville R, Blow JJ, Gartner A et al. CDC-48/p97 coordinates CDT-1 degradation with GINS chromatin dissociation to ensure faithful DNA replication. Mol Cell 2011; 44: 85–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Meyer H, Bug M, Bremer S . Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 2012; 14: 117–123.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tan MK, Lim HJ, Harper JW . SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation. Mol Cell Biol 2011; 31: 3687–3699.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Mallette FA, Richard S . K48-linked ubiquitination and protein degradation regulate 53BP1 recruitment at DNA damage sites. Cell Res 2012; 22: 1221–1223.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Sauer RT, Bolon DN, Burton BM, Burton RE, Flynn JM, Grant RA et al. Sculpting the proteome with AAA(+) proteases and disassembly machines. Cell 2004; 119: 9–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Richly H, Rape M, Braun S, Rumpf S, Hoege C, Jentsch S . A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 2005; 120: 73–84.

    CAS  PubMed  Google Scholar 

  90. Wilcox AJ, Laney JD . A ubiquitin-selective AAA-ATPase mediates transcriptional switching by remodelling a repressor-promoter DNA complex. Nat Cell Biol 2009; 11: 1481–1486.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Rumpf S, Jentsch S . Functional division of substrate processing cofactors of the ubiquitin-selective Cdc48 chaperone. Mol Cell 2006; 21: 261–269.

    CAS  PubMed  Google Scholar 

  92. Verma R, Oania R, Fang R, Smith GT, Deshaies RJ . Cdc48/p97 mediates UV-dependent turnover of RNA Pol II. Mol Cell 2011; 41: 82–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Ernst R, Claessen JH, Mueller B, Sanyal S, Spooner E, van der Veen AG et al. Enzymatic blockade of the ubiquitin-proteasome pathway. PLoS Biol 2011; 8: e1000605.

    PubMed  Google Scholar 

  94. Livingstone M, Ruan H, Weiner J, Clauser KR, Strack P, Jin S et al. Valosin-containing protein phosphorylation at Ser784 in response to DNA damage. Cancer Res 2005; 65: 7533–7540.

    CAS  PubMed  Google Scholar 

  95. Zhang H, Wang Q, Kajino K, Greene MI . VCP, a weak ATPase involved in multiple cellular events, interacts physically with BRCA1 in the nucleus of living cells. DNA Cell Biol 2000; 19: 253–263.

    CAS  PubMed  Google Scholar 

  96. Indig FE, Partridge JJ, von Kobbe C, Aladjem MI, Latterich M, Bohr VA . Werner syndrome protein directly binds to the AAA ATPase p97/VCP in an ATP-dependent fashion. J Struct Biol 2004; 146: 251–259.

    CAS  PubMed  Google Scholar 

  97. Yamada T, Okuhara K, Iwamatsu A, Seo H, Ohta K, Shibata T et al. p97 ATPase, an ATPase involved in membrane fusion, interacts with DNA unwinding factor (DUF) that functions in DNA replication. FEBS Lett 2000; 466: 287–291.

    CAS  PubMed  Google Scholar 

  98. Min J, Allali-Hassani A, Nady N, Qi C, Ouyang H, Liu Y et al. L3MBTL1 recognition of mono- and dimethylated histones. Nat Struct Mol Biol 2007; 14: 1229–1230.

    CAS  PubMed  Google Scholar 

  99. Lok GT, Sy SM, Dong SS, Ching YP, Tsao SW, Thomson TM et al. Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation. Nucleic Acids Res 2011; 40: 196–205.

    PubMed  PubMed Central  Google Scholar 

  100. Dimitrova N, Chen YC, Spector DL, de Lange T . 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 2008; 456: 524–528.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bothmer A, Robbiani DF, Di Virgilio M, Bunting SF, Klein IA, Feldhahn N et al. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. Mol Cell 2011; 42: 319–329.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hu X, Paul A, Wang B . Rap80 Recruitment to DNA double strand breaks requires binding to both sumo- and ubiquitin-conjugates. J Biol Chem 2012; 287: 25510–25519.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Guzzo CM, Berndsen CE, Zhu J, Gupta V, Datta A, Greenberg RA 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 2012; 5: ra88.

    PubMed  PubMed Central  Google Scholar 

  104. Wang B, Hurov K, Hofmann K, Elledge SJ . NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev 2009; 23: 729–739.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Mok MT, Henderson BR . A comparison of BRCA1 nuclear localization with 14 DNA damage response proteins and domains: identification of specific differences between BRCA1 and 53BP1 at DNA damage-induced foci. Cell Signal 2010; 22: 47–56.

    CAS  PubMed  Google Scholar 

  106. Chapman JR, Sossick AJ, Boulton SJ, Jackson SP . BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J Cell Sci 2012; 125 (Pt 15): 3529–3534.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 2010; 17: 688–695.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 2010; 141: 243–254.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol Cell 2009; 35: 534–541.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Gudjonsson T, Altmeyer M, Savic V, Toledo L, Dinant C, Grofte M et al. TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes. Cell 2012; 150: 697–709.

    CAS  PubMed  Google Scholar 

  111. Pegoraro G, Voss TC, Martin SE, Tuzmen P, Guha R, Misteli T . Identification of mammalian protein quality control factors by high-throughput cellular imaging. PLoS ONE 2012; 7: e31684.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kristensen CN, Bystol KM, Li B, Serrano L, Brenneman MA . Depletion of DSS1 protein disables homologous recombinational repair in human cells. Mutat Res 2010; 694: 60–64.

    CAS  PubMed  Google Scholar 

  113. Zhou Q, Kojic M, Cao Z, Lisby M, Mazloum NA, Holloman WK . Dss1 interaction with Brh2 as a regulatory mechanism for recombinational repair. Mol Cell Biol 2007; 27: 2512–2526.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Kojic M, Zhou Q, Lisby M, Holloman WK . Brh2-Dss1 interplay enables properly controlled recombination in Ustilago maydis. Mol Cell Biol 2005; 25: 2547–2557.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Liu J, Doty T, Gibson B, Heyer WD . Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat Struct Mol Biol 2010; 17: 1260–1262.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Takeshita T, Wu W, Koike A, Fukuda M, Ohta T . Perturbation of DNA repair pathways by proteasome inhibitors corresponds to enhanced chemosensitivity of cells to DNA damage-inducing agents. Cancer Chemotherapy Pharmacol 2009; 64: 1039–1046.

    CAS  Google Scholar 

  117. Neri P, Ren L, Gratton K, Stebner E, Johnson J, Klimowicz A et al. Bortezomib-induced ‘BRCAness’ sensitizes multiple myeloma cells to PARP inhibitors. Blood 2011; 118: 6368–6379.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906–917.

    CAS  PubMed  Google Scholar 

  119. Chen Q, Van der Sluis PC, Boulware D, Hazlehurst LA, Dalton WS . The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. Blood 2005; 106: 698–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Beaven AW, Shea TC, Moore DT, Feldman T, Ivanova A, Ferraro M et al. A phase I study evaluating ibritumomab tiuxetan (Zevalin(R)) in combination with bortezomib (Velcade(R)) in relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma. Leukemia Lymphoma 2012; 53: 254–258.

    CAS  PubMed  Google Scholar 

  121. Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012; 120: 947–959.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Dalla Via L, Nardon C, Fregona D . Targeting the ubiquitin-proteasome pathway with inorganic compounds to fight cancer: a challenge for the future. Future Med Chem 2012; 4: 525–543.

    CAS  PubMed  Google Scholar 

  123. Ramchandren R . Advances in the treatment of relapsed or refractory Hodgkin’s lymphoma. Oncol 2012; 17: 367–376.

    CAS  Google Scholar 

  124. Cvek B . Proteasome inhibitors. Prog Mol Biol Translational Sci 2012; 109: 161–226.

    CAS  Google Scholar 

  125. D’Arcy P, Linder S . Proteasome deubiquitinases as novel targets for cancer therapy. Int J Biochem Cell Biol 2012; 44: 1729–1738.

    PubMed  Google Scholar 

  126. Cvek B . Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. Curr Cancer Drug Targets 2011; 11: 332–337.

    CAS  PubMed  Google Scholar 

  127. Gallery M, Blank JL, Lin Y, Gutierrez JA, Pulido JC, Rappoli D et al. The JAMM motif of human deubiquitinase Poh1 is essential for cell viability. Mol Cancer Ther 2007; 6: 262–268.

    CAS  PubMed  Google Scholar 

  128. Lasker K, Forster F, Bohn S, Walzthoeni T, Villa E, Unverdorben P et al. Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach. Proc Natl Acad Sci USA 2012; 109: 1380–1387.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Lander GC, Estrin E, Matyskiela ME, Bashore C, Nogales E, Martin A . Complete subunit architecture of the proteasome regulatory particle. Nature 2012; 482: 186–191.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 2005; 123: 773–786.

    CAS  PubMed  Google Scholar 

  131. Verma R, Aravind L, Oania R, McDonald WH, Yates JR, Koonin EV et al. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 2002; 298: 611–615.

    CAS  PubMed  Google Scholar 

  132. Yao T, Cohen RE . A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 2002; 419: 403–407.

    CAS  PubMed  Google Scholar 

  133. Nabhan JF, Ribeiro P . The 19 S proteasomal subunit POH1 contributes to the regulation of c-Jun ubiquitination, stability, and subcellular localization. J Biol Chem 2006; 281: 16099–16107.

    CAS  PubMed  Google Scholar 

  134. Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-[kappa]B signalling. Nature 2004; 430: 694–699.

    CAS  PubMed  Google Scholar 

  135. Burnett B, Li F, Pittman RN . The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Human Mol Genet 2003; 12: 3195–3205.

    CAS  Google Scholar 

  136. Scheel H, Tomiuk S, Hofmann K . Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics. Human Mol Genet 2003; 12: 2845–2852.

    CAS  Google Scholar 

  137. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT . The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and parkinson’s disease susceptibility. Cell 2002; 111: 209–218.

    CAS  PubMed  Google Scholar 

  138. Lam YA, Xu W, DeMartino GN, Cohen RE . Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature 1997; 385: 737–740.

    CAS  PubMed  Google Scholar 

  139. Nishio K, Kim SW, Kawai K, Mizushima T, Yamane T, Hamazaki J et al. Crystal structure of the de-ubiquitinating enzyme UCH37 (human UCH-L5) catalytic domain. Biochem Biophys Res Commun 2009; 390: 855–860.

    CAS  PubMed  Google Scholar 

  140. Schoenfeld AR, Apgar S, Dolios G, Wang R, Aaronson SA . BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol Cell Biol 2004; 24: 7444–7455.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Brummelkamp TR, Nijman SMB, Dirac AMG, Bernards R . Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-[kappa]B. Nature 2003; 424: 797–801.

    CAS  PubMed  Google Scholar 

  142. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G . The tumour suppressor CYLD negatively regulates NF-[kappa]B signalling by deubiquitination. Nature 2003; 424: 801–805.

    CAS  PubMed  Google Scholar 

  143. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G . CYLD is a deubiquitinating enzyme that negatively regulates NF-[kappa]B activation by TNFR family members. Nature 2003; 424: 793–796.

    CAS  PubMed  Google Scholar 

  144. Nijman SMB, Huang TT, Dirac AMG, Brummelkamp TR, Kerkhoven RM, D’Andrea AD et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell 2005; 17: 331–339.

    CAS  PubMed  Google Scholar 

  145. Russell NS, Wilkinson KD . Identification of a novel 29-linked polyubiquitin binding protein, Ufd3, using polyubiquitin chain analogues†,‡. Biochemistry 2004; 43: 4844–4854.

    CAS  PubMed  Google Scholar 

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Acknowledgements

HRS is supported by the Breast Cancer Campaign Grant 2010NovPhD02.

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    H R Stone & J R Morris

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Stone, H., Morris, J. DNA damage emergency: cellular garbage disposal to the rescue?. Oncogene 33, 805–813 (2014). https://doi.org/10.1038/onc.2013.60

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