Ubiquitin-SUMO Circuitry Controls Activated Fanconi Anemia ID Complex Dosage in Response to DNA Damage

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Jan 6

PMID 25557546

Citations 78

Authors

Ian Gibbs-Seymour

Yasuyoshi Oka

Eeson Rajendra

Brian T Weinert

Lori A Passmore

Ketan J Patel

Jesper V Olsen

Chunaram Choudhary

Simon Bekker-Jensen

Niels Mailand

Affiliations

Soon will be listed here.

Abstract

We show that central components of the Fanconi anemia (FA) DNA repair pathway, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to replication fork stalling. The ID complex is SUMOylated in a manner that depends on the ATR kinase, the FA ubiquitin ligase core complex, and the SUMO E3 ligases PIAS1/PIAS4 and is antagonized by the SUMO protease SENP6. SUMOylation of the ID complex drives substrate selectivity by triggering its polyubiquitylation by the SUMO-targeted ubiquitin ligase RNF4 to promote its removal from sites of DNA damage via the DVC1-p97 ubiquitin segregase complex. Deregulation of ID complex SUMOylation compromises cell survival following replication stress. Our results uncover a regulatory role for SUMOylation in the FA pathway, and we propose that ubiquitin-SUMO signaling circuitry is a mechanism that contributes to the balance of activated ID complex dosage at sites of DNA damage.

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References

Barysch S, Dittner C, Flotho A, Becker J, Melchior F . Identification and analysis of endogenous SUMO1 and SUMO2/3 targets in mammalian cells and tissues using monoclonal antibodies. Nat Protoc. 2014; 9(4):896-909. DOI: 10.1038/nprot.2014.053. View

Toledo L, Altmeyer M, Rask M, Lukas C, Larsen D, Povlsen L . ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell. 2013; 155(5):1088-103. DOI: 10.1016/j.cell.2013.10.043. View

Adamo A, Collis S, Adelman C, Silva N, Horejsi Z, Ward J . Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol Cell. 2010; 39(1):25-35. DOI: 10.1016/j.molcel.2010.06.026. View

Pace P, Mosedale G, Hodskinson M, Rosado I, Sivasubramaniam M, Patel K . Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science. 2010; 329(5988):219-23. DOI: 10.1126/science.1192277. View

Ciccia A, Elledge S . The DNA damage response: making it safe to play with knives. Mol Cell. 2010; 40(2):179-204. PMC: 2988877. DOI: 10.1016/j.molcel.2010.09.019. View

Danielsen J, Sylvestersen K, Bekker-Jensen S, Szklarczyk D, Poulsen J, Horn H . Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level. Mol Cell Proteomics. 2010; 10(3):M110.003590. PMC: 3047152. DOI: 10.1074/mcp.M110.003590. View

Tatham M, Matic I, Mann M, Hay R . Comparative proteomic analysis identifies a role for SUMO in protein quality control. Sci Signal. 2011; 4(178):rs4. DOI: 10.1126/scisignal.2001484. View

Joo W, Xu G, Persky N, Smogorzewska A, Rudge D, Buzovetsky O . Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway. Science. 2011; 333(6040):312-6. PMC: 3310437. DOI: 10.1126/science.1205805. View

Wagner S, Beli P, Weinert B, Nielsen M, Cox J, Mann M . A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol Cell Proteomics. 2011; 10(10):M111.013284. PMC: 3205876. DOI: 10.1074/mcp.M111.013284. View

10.

Zhang J, Walter J . Mechanism and regulation of incisions during DNA interstrand cross-link repair. DNA Repair (Amst). 2014; 19:135-42. PMC: 4076290. DOI: 10.1016/j.dnarep.2014.03.018. View

11.

Rajendra E, Oestergaard V, Langevin F, Wang M, Dornan G, Patel K . The genetic and biochemical basis of FANCD2 monoubiquitination. Mol Cell. 2014; 54(5):858-69. PMC: 4051986. DOI: 10.1016/j.molcel.2014.05.001. View

12.

Hendriks I, DSouza R, Yang B, Verlaan-de Vries M, Mann M, Vertegaal A . Uncovering global SUMOylation signaling networks in a site-specific manner. Nat Struct Mol Biol. 2014; 21(10):927-36. PMC: 4259010. DOI: 10.1038/nsmb.2890. View

13.

Ndoja A, Cohen R, Yao T . Ubiquitin signals proteolysis-independent stripping of transcription factors. Mol Cell. 2014; 53(6):893-903. PMC: 4005849. DOI: 10.1016/j.molcel.2014.02.002. View

14.

Rojas-Fernandez A, Plechanovova A, Hattersley N, Jaffray E, Tatham M, Hay R . SUMO chain-induced dimerization activates RNF4. Mol Cell. 2014; 53(6):880-92. PMC: 3991395. DOI: 10.1016/j.molcel.2014.02.031. View

15.

Klein Douwel D, Boonen R, Long D, Szypowska A, Raschle M, Walter J . XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol Cell. 2014; 54(3):460-71. PMC: 5067070. DOI: 10.1016/j.molcel.2014.03.015. View

16.

Hodskinson M, Silhan J, Crossan G, Garaycoechea J, Mukherjee S, Johnson C . Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Mol Cell. 2014; 54(3):472-84. PMC: 4017094. DOI: 10.1016/j.molcel.2014.03.014. 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.

Akkari Y, Bateman R, Reifsteck C, DAndrea A, Olson S, Grompe M . The 4N cell cycle delay in Fanconi anemia reflects growth arrest in late S phase. Mol Genet Metab. 2001; 74(4):403-12. DOI: 10.1006/mgme.2001.3259. View

19.

Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald 3rd E, Hurov K, Luo J . Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007; 129(2):289-301. PMC: 2175179. DOI: 10.1016/j.cell.2007.03.009. View

20.

Cohn M, Kowal P, Yang K, Haas W, Huang T, Gygi S . A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell. 2007; 28(5):786-97. DOI: 10.1016/j.molcel.2007.09.031. View