Regulation of DNA Repair Through DeSUMOylation and SUMOylation of Replication Protein A Complex

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Aug 14

PMID 20705237

Citations 118

Authors

Hong Dou

Chao Huang

Melissa Singh

Phillip B Carpenter

Edward T H Yeh

Affiliations

Soon will be listed here.

Abstract

The replication protein A complex (RPA) plays a crucial role in DNA replication and damage response. However, it is not known whether this complex is regulated by the SUMOylation pathway. Here, we show that the 70 kDa subunit of RPA (RPA70) associates with a Sentrin/SUMO-specific protease, SENP6, in the nucleus to maintain RPA70 in a hypoSUMOylated state during S phase. Campothecin (CPT), an inducer of replication stress, dissociates SENP6 from RPA70, allowing RPA70 to be modified by a small ubiquitin-like modifier 2/3 (SUMO-2/3). RPA70 SUMOylation facilitates recruitment of Rad51 to the DNA damage foci to initiate DNA repair through homologous recombination (HR). Cell lines that expressed a RPA70 mutant that cannot be SUMOylated are defective in HR and have a marked increase in sensitivity to CPT. These results demonstrate that SUMOylation status of RPA70 plays a critical role in the regulation of DNA repair through homologous recombination.

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References

Gong L, Yeh E . Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3. J Biol Chem. 2006; 281(23):15869-77. DOI: 10.1074/jbc.M511658200. View

Cheng J, Kang X, Zhang S, Yeh E . SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell. 2007; 131(3):584-95. PMC: 2128732. DOI: 10.1016/j.cell.2007.08.045. View

Jeggo P, Lobrich M . Radiation-induced DNA damage responses. Radiat Prot Dosimetry. 2007; 122(1-4):124-7. DOI: 10.1093/rpd/ncl495. View

Ouyang K, Woo L, Zhu J, Huo D, Matunis M, Ellis N . SUMO modification regulates BLM and RAD51 interaction at damaged replication forks. PLoS Biol. 2009; 7(12):e1000252. PMC: 2779653. DOI: 10.1371/journal.pbio.1000252. View

Hiom K . Recombination: homologous recombination branches out. Curr Biol. 2001; 11(7):R278-80. DOI: 10.1016/s0960-9822(01)00138-5. View

Branzei D, Foiani M . The DNA damage response during DNA replication. Curr Opin Cell Biol. 2005; 17(6):568-75. DOI: 10.1016/j.ceb.2005.09.003. View

Fanning E, Klimovich V, Nager A . A dynamic model for replication protein A (RPA) function in DNA processing pathways. Nucleic Acids Res. 2006; 34(15):4126-37. PMC: 1616954. DOI: 10.1093/nar/gkl550. View

Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller K, Jackson S . Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature. 2009; 462(7275):935-9. PMC: 2904806. DOI: 10.1038/nature08657. View

Yu D, Sonoda E, Takeda S, Huang C, Pellegrini L, Blundell T . Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2. Mol Cell. 2003; 12(4):1029-41. DOI: 10.1016/s1097-2765(03)00394-0. View

10.

Shrivastav M, De Haro L, Nickoloff J . Regulation of DNA double-strand break repair pathway choice. Cell Res. 2007; 18(1):134-47. DOI: 10.1038/cr.2007.111. View

11.

Galletto R, Kowalczykowski S . RecA. Curr Biol. 2007; 17(11):R395-7. DOI: 10.1016/j.cub.2007.03.009. View

12.

Burgess R, Rahman S, Lisby M, Rothstein R, Zhao X . The Slx5-Slx8 complex affects sumoylation of DNA repair proteins and negatively regulates recombination. Mol Cell Biol. 2007; 27(17):6153-62. PMC: 1952148. DOI: 10.1128/MCB.00787-07. View

13.

Meulmeester E, Melchior F . Cell biology: SUMO. Nature. 2008; 452(7188):709-11. DOI: 10.1038/452709a. View

14.

Di Bacco A, Ouyang J, Lee H, Catic A, Ploegh H, Gill G . The SUMO-specific protease SENP5 is required for cell division. Mol Cell Biol. 2006; 26(12):4489-98. PMC: 1489136. DOI: 10.1128/MCB.02301-05. View

15.

Wu X, Yang Z, Liu Y, Zou Y . Preferential localization of hyperphosphorylated replication protein A to double-strand break repair and checkpoint complexes upon DNA damage. Biochem J. 2005; 391(Pt 3):473-80. PMC: 1276948. DOI: 10.1042/BJ20050379. View

16.

San Filippo J, Sung P, Klein H . Mechanism of eukaryotic homologous recombination. Annu Rev Biochem. 2008; 77:229-57. DOI: 10.1146/annurev.biochem.77.061306.125255. View

17.

Dimitrova D, Gilbert D . Stability and nuclear distribution of mammalian replication protein A heterotrimeric complex. Exp Cell Res. 2000; 254(2):321-7. DOI: 10.1006/excr.1999.4770. View

18.

Dimitrova D, Todorov I, Melendy T, Gilbert D . Mcm2, but not RPA, is a component of the mammalian early G1-phase prereplication complex. J Cell Biol. 1999; 146(4):709-22. PMC: 2156148. DOI: 10.1083/jcb.146.4.709. View

19.

Sugiyama T, Kowalczykowski S . Rad52 protein associates with replication protein A (RPA)-single-stranded DNA to accelerate Rad51-mediated displacement of RPA and presynaptic complex formation. J Biol Chem. 2002; 277(35):31663-72. DOI: 10.1074/jbc.M203494200. View

20.

Li S, Hochstrasser M . The yeast ULP2 (SMT4) gene encodes a novel protease specific for the ubiquitin-like Smt3 protein. Mol Cell Biol. 2000; 20(7):2367-77. PMC: 85410. DOI: 10.1128/MCB.20.7.2367-2377.2000. View