Deubiquitination of FANCD2 is Required for DNA Crosslink Repair

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2007 Dec 18

PMID 18082605

Citations 119

Authors

Vibe H Oestergaard

Frederic Langevin

Hendrik J Kuiken

Paul Pace

Wojciech Niedzwiedz

Laura J Simpson

Mioko Ohzeki

Minoru Takata

Julian E Sale

Ketan J Patel

Affiliations

Soon will be listed here.

Abstract

Monoubiquitination of FANCD2 and PCNA promotes DNA repair. It causes chromatin accumulation of FANCD2 and facilitates PCNA's recruitment of translesion polymerases to stalled replication. USP1, a protease that removes monoubiquitin from FANCD2 and PCNA, was thought to reverse the DNA damage response of these substrates. We disrupted USP1 in chicken cells to dissect its role in a stable genetic system. USP1 ablation increases FANCD2 and PCNA monoubiquitination but unexpectedly results in DNA crosslinker sensitivity. This defective DNA repair is associated with constitutively chromatin-bound, monoubiquitinated FANCD2. In contrast, persistent PCNA monoubiquitination has negligible impact on DNA repair or mutagenesis. USP1 was previously shown to autocleave after DNA damage. In DT40, USP1 autocleavage is not stimulated by DNA damage, and expressing a noncleavable mutant in the USP1 knockout strain partially rescues crosslinker sensitivity. We conclude that efficient DNA crosslink repair requires FANCD2 deubiquitination, whereas FANCD2 monoubiquitination is not dependent on USP1 autocleavage.

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References

Haracska L, Unk I, Prakash L, Prakash S . Ubiquitylation of yeast proliferating cell nuclear antigen and its implications for translesion DNA synthesis. Proc Natl Acad Sci U S A. 2006; 103(17):6477-82. PMC: 1458909. DOI: 10.1073/pnas.0510924103. View

Taniguchi T, Garcia-Higuera I, Andreassen P, Gregory R, Grompe M, DAndrea A . S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood. 2002; 100(7):2414-20. DOI: 10.1182/blood-2002-01-0278. View

Ulrich H . Deubiquitinating PCNA: a downside to DNA damage tolerance. Nat Cell Biol. 2006; 8(4):303-5. DOI: 10.1038/ncb0406-303. View

Montes de Oca R, Andreassen P, Margossian S, Gregory R, Taniguchi T, Wang X . Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin. Blood. 2004; 105(3):1003-9. DOI: 10.1182/blood-2003-11-3997. View

Friedberg E . Reversible monoubiquitination of PCNA: A novel slant on regulating translesion DNA synthesis. Mol Cell. 2006; 22(2):150-2. DOI: 10.1016/j.molcel.2006.04.002. View

Hoege C, Pfander B, Moldovan G, Pyrowolakis G, Jentsch S . RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature. 2002; 419(6903):135-41. DOI: 10.1038/nature00991. View

Huang T, DAndrea A . Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol. 2006; 7(5):323-34. DOI: 10.1038/nrm1908. View

Zhou B, Elledge S . The DNA damage response: putting checkpoints in perspective. Nature. 2000; 408(6811):433-9. DOI: 10.1038/35044005. View

Di Noia J, Neuberger M . Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature. 2002; 419(6902):43-8. DOI: 10.1038/nature00981. View

10.

Bienko M, Green C, Crosetto N, Rudolf F, Zapart G, Coull B . Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science. 2005; 310(5755):1821-4. DOI: 10.1126/science.1120615. View

11.

Sale J, Calandrini D, Takata M, Takeda S, Neuberger M . Ablation of XRCC2/3 transforms immunoglobulin V gene conversion into somatic hypermutation. Nature. 2001; 412(6850):921-6. DOI: 10.1038/35091100. View

12.

Meetei A, Medhurst A, Ling C, Xue Y, Singh T, Bier P . A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005; 37(9):958-63. PMC: 2704909. DOI: 10.1038/ng1626. View

13.

Arakawa H, Moldovan G, Saribasak H, Saribasak N, Jentsch S, Buerstedde J . A role for PCNA ubiquitination in immunoglobulin hypermutation. PLoS Biol. 2006; 4(11):e366. PMC: 1618868. DOI: 10.1371/journal.pbio.0040366. View

14.

Kawamoto T, Araki K, Sonoda E, Yamashita Y, Harada K, Kikuchi K . Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell. 2005; 20(5):793-9. DOI: 10.1016/j.molcel.2005.10.016. View

15.

Di Noia J, Rada C, Neuberger M . SMUG1 is able to excise uracil from immunoglobulin genes: insight into mutation versus repair. EMBO J. 2006; 25(3):585-95. PMC: 1383525. DOI: 10.1038/sj.emboj.7600939. View

16.

Garg P, Burgers P . Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases eta and REV1. Proc Natl Acad Sci U S A. 2005; 102(51):18361-6. PMC: 1317920. DOI: 10.1073/pnas.0505949102. View

17.

Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn M, Timmers C, Hejna J . Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001; 7(2):249-62. DOI: 10.1016/s1097-2765(01)00173-3. View

18.

Nijman S, Luna-Vargas M, Velds A, Brummelkamp T, Dirac A, Sixma T . A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005; 123(5):773-86. DOI: 10.1016/j.cell.2005.11.007. View

19.

Buerstedde J, REYNAUD C, Humphries E, Olson W, Ewert D, Weill J . Light chain gene conversion continues at high rate in an ALV-induced cell line. EMBO J. 1990; 9(3):921-7. PMC: 551754. DOI: 10.1002/j.1460-2075.1990.tb08190.x. View

20.

Nijman S, Huang T, Dirac A, Brummelkamp T, Kerkhoven R, DAndrea A . The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005; 17(3):331-9. DOI: 10.1016/j.molcel.2005.01.008. View