Human MMS21/NSE2 is a SUMO Ligase Required for DNA Repair

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2005 Aug 2

PMID 16055714

Citations 130

Authors

Patrick Ryan Potts

Hongtao Yu

Affiliations

Soon will be listed here.

Abstract

DNA repair is required for the genomic stability and well-being of an organism. In yeasts, a multisubunit complex consisting of SMC5, SMC6, MMS21/NSE2, and other non-SMC proteins is required for DNA repair through homologous recombination. The yeast MMS21 protein is a SUMO ligase. Here we show that the human homolog of MMS21 is also a SUMO ligase. hMMS21 stimulates sumoylation of hSMC6 and the DNA repair protein TRAX. Depletion of hMMS21 by RNA interference (RNAi) sensitizes HeLa cells toward DNA damage-induced apoptosis. Ectopic expression of wild-type hMMS21, but not its ligase-inactive mutant, rescues this hypersensitivity of hMMS21-RNAi cells. ATM/ATR are hyperactivated in hMMS21-RNAi cells upon DNA damage. Consistently, hMMS21-RNAi cells show an increased number of phospho-CHK2 foci. Finally, we show that hMMS21-RNAi cells show a decreased capacity to repair DNA lesions as measured by the comet assay. Our findings suggest that the human SMC5/6 complex and the SUMO ligase activity of hMMS21 are required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair in human cells.

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References

Kim S, Lim D, Canman C, Kastan M . Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem. 1999; 274(53):37538-43. DOI: 10.1074/jbc.274.53.37538. View

Torres-Rosell J, Machin F, Farmer S, Jarmuz A, Eydmann T, Dalgaard J . SMC5 and SMC6 genes are required for the segregation of repetitive chromosome regions. Nat Cell Biol. 2005; 7(4):412-9. DOI: 10.1038/ncb1239. View

Mao Y, Sun M, Desai S, Liu L . SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci U S A. 2000; 97(8):4046-51. PMC: 18143. DOI: 10.1073/pnas.080536597. View

Koshland D, Guacci V . Sister chromatid cohesion: the beginning of a long and beautiful relationship. Curr Opin Cell Biol. 2000; 12(3):297-301. DOI: 10.1016/s0955-0674(00)00092-2. View

Melchionna R, Chen X, Blasina A, McGowan C . Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1. Nat Cell Biol. 2000; 2(10):762-5. DOI: 10.1038/35036406. View

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

Khanna K, Jackson S . DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001; 27(3):247-54. DOI: 10.1038/85798. View

Elbashir S, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T . Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001; 411(6836):494-8. DOI: 10.1038/35078107. View

Taylor E, Moghraby J, Lees J, Smit B, Moens P, Lehmann A . Characterization of a novel human SMC heterodimer homologous to the Schizosaccharomyces pombe Rad18/Spr18 complex. Mol Biol Cell. 2001; 12(6):1583-94. PMC: 37326. DOI: 10.1091/mbc.12.6.1583. View

10.

Johnson E, Gupta A . An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell. 2001; 106(6):735-44. DOI: 10.1016/s0092-8674(01)00491-3. View

11.

Ho J, Warr N, Shimizu H, Watts F . SUMO modification of Rad22, the Schizosaccharomyces pombe homologue of the recombination protein Rad52. Nucleic Acids Res. 2001; 29(20):4179-86. PMC: 60211. DOI: 10.1093/nar/29.20.4179. View

12.

Ward I, Wu X, Chen J . Threonine 68 of Chk2 is phosphorylated at sites of DNA strand breaks. J Biol Chem. 2001; 276(51):47755-8. DOI: 10.1074/jbc.C100587200. View

13.

Pichler A, Gast A, Seeler J, Dejean A, Melchior F . The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell. 2002; 108(1):109-20. DOI: 10.1016/s0092-8674(01)00633-x. View

14.

Hirano T . The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair. Genes Dev. 2002; 16(4):399-414. DOI: 10.1101/gad.955102. View

15.

Taylor D, Ho J, Oliver A, Watts F . Cell-cycle-dependent localisation of Ulp1, a Schizosaccharomyces pombe Pmt3 (SUMO)-specific protease. J Cell Sci. 2002; 115(Pt 6):1113-22. DOI: 10.1242/jcs.115.6.1113. View

16.

Hardeland U, Steinacher R, Jiricny J, Schar P . Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. EMBO J. 2002; 21(6):1456-64. PMC: 125358. DOI: 10.1093/emboj/21.6.1456. View

17.

Fujioka Y, Kimata Y, Nomaguchi K, Watanabe K, Kohno K . Identification of a novel non-structural maintenance of chromosomes (SMC) component of the SMC5-SMC6 complex involved in DNA repair. J Biol Chem. 2002; 277(24):21585-91. DOI: 10.1074/jbc.M201523200. View

18.

Nasmyth K . Segregating sister genomes: the molecular biology of chromosome separation. Science. 2002; 297(5581):559-65. DOI: 10.1126/science.1074757. View

19.

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

20.

DiTullio Jr R, Mochan T, Venere M, Bartkova J, Sehested M, Bartek J . 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat Cell Biol. 2002; 4(12):998-1002. DOI: 10.1038/ncb892. View