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Published 29 August 2005. doi:10.1083/jcb.200502113
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 5, 745-755
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Article

 Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A

Parker L. Andersen1, Honglin Zhou2, Landon Pastushok1, Trevor Moraes3, Sean McKenna3, Barry Ziola4, Michael J. Ellison3, Vishva M. Dixit2, and Wei Xiao1

1 Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
4 Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
2 Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080
3 Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

Correspondence to Wei Xiao: wei.xiao{at}usask.ca

Ubc13, a ubiquitin-conjugating enzyme (Ubc), requires the presence of a Ubc variant (Uev) for polyubiquitination. Uevs, although resembling Ubc in sequence and structure, lack the active site cysteine residue and are catalytically inactive. The yeast Uev (Mms2) incites noncanonical Lys63-linked polyubiquitination by Ubc13, whereas the increased diversity of Uevs in higher eukaryotes suggests an unexpected complication in ubiquitination. In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2. Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains. Functionally, we describe that Ubc13–Mms2 is required for DNA damage repair but not nuclear factor {kappa}B (NF-{kappa}B) activation, whereas Ubc13–Uev1A is involved in NF-{kappa}B activation but not DNA repair. Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination.

P.L. Andersen and H. Zhou contributed equally to this paper.

Abbreviations used in this paper: CPT, camptothecin; DSB, double-stranded break; ICC, immunocytochemistry; LPS, lipopolysaccharide; MMS, methyl methanesulfonate; PCNA, proliferating cell nuclear antigen; PRR, postreplication repair; RNAi, RNA interference; siRNA, small interference RNA; Ub, ubiquitin.


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