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Molecular and Cellular Biology, March 2006, p. 1786-1794, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1786-1794.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

SUMO Modification of Human XRCC4 Regulates Its Localization and Function in DNA Double-Strand Break Repair{dagger}

Vyacheslav Yurchenko, Zhu Xue, and Moshe J. Sadofsky*

Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461

Received 16 May 2005/ Returned for modification 30 June 2005/ Accepted 8 December 2005

The nonhomologous end-joining (NHEJ) pathway is responsible for rejoining the majority of double-strand breaks in mammalian cells, including the programmed breaks introduced by V(D)J recombination. The regulation of the enzymatic activities associated with this recombination pathway is still largely unknown. Here we report that human XRCC4 (for X-ray cross-complementation group 4), a protein essential for NHEJ, is subject to posttranslational protein modification. The modifier peptide, SUMO, can be added to XRCC4 both in vitro and in vivo. The site of modification is mapped to lysine 210 by using specific mutagenesis. A protein mutated such that it cannot be SUMOylated remains localized in the cytoplasm rather than accumulating in the nucleus. Cells expressing only the mutated protein are radiation sensitive and fail to complete V(D)J recombination. Genetic fusion of the SUMO sequence to the C terminus of the mutant restores nuclear localization and radiation resistance. The modification may serve a regulatory role. Our finding fits with an emerging literature associating SUMO modification with the control of the repair and recombination associated with DNA breaks.

* Corresponding author. Mailing address: Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2222. Fax: (718) 430-8541. E-mail: sadofsky{at}aecom.yu.edu.

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

Molecular and Cellular Biology, March 2006, p. 1786-1794, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1786-1794.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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