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Vol. 19, Issue 10, 4099-4109, October 2008

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Nse1 RING-like Domain Supports Functions of the Smc5-Smc6 Holocomplex in Genome Stability

Stephanie Pebernard^*, J. Jefferson P. Perry^*,, John A. Tainer^*,, and Michael N. Boddy^*

*Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; The School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappanna (PO) Kollam, Kerala 690-525, India; and Lawrence Berkeley National Laboratory, Berkeley, CA, 94720

Submitted February 29, 2008; Accepted July 21, 2008
Monitoring Editor: Orna Cohen-Fix

The Smc5-Smc6 holocomplex plays essential but largely enigmatic roles in chromosome segregation, and facilitates DNA repair. The Smc5-Smc6 complex contains six conserved non-SMC subunits. One of these, Nse1, contains a RING-like motif that often confers ubiquitin E3 ligase activity. We have functionally characterized the Nse1 RING-like motif, to determine its contribution to the chromosome segregation and DNA repair roles of Smc5-Smc6. Strikingly, whereas a full deletion of nse1 is lethal, the Nse1 RING-like motif is not essential for cellular viability. However, Nse1 RING mutant cells are hypersensitive to a broad spectrum of genotoxic stresses, indicating that the Nse1 RING motif promotes DNA repair functions of Smc5-Smc6. We tested the ability of both human and yeast Nse1 to mediate ubiquitin E3 ligase activity in vitro and found no detectable activity associated with full-length Nse1 or the isolated RING domains. Interestingly, however, the Nse1 RING-like domain is required for normal Nse1-Nse3-Nse4 trimer formation in vitro and for damage-induced recruitment of Nse4 and Smc5 to subnuclear foci in vivo. Thus, we propose that the Nse1 RING-like motif is a protein–protein interaction domain required for Smc5-Smc6 holocomplex integrity and recruitment to, or retention at, DNA lesions.

Address correspondence to: Michael N. Boddy (nboddy{at}scripps.edu)

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