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Molecular and Cellular Biology, August 2005, p. 7021-7032, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7021-7032.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human MMS21/NSE2 Is a SUMO Ligase Required for DNA Repair{dagger}

Patrick Ryan Potts and Hongtao Yu*

Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, Texas 75390

Received 25 February 2005/ Returned for modification 18 March 2005/ Accepted 24 May 2005

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.

* Corresponding author. Mailing address: Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041. Phone: (214) 645-6161. Fax: (214) 645-6156. E-mail: hongtao.yu{at}utsouthwestern.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2005, p. 7021-7032, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.7021-7032.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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