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Vol. 20, Issue 1, 1-9, January 1, 2009

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Novel Control of S Phase of the Cell Cycle by Ubiquitin-conjugating Enzyme H7

Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111

Submitted January 17, 2008; Revised October 6, 2008; Accepted October 9, 2008
Monitoring Editor: William P. Tansey

Timely degradation of regulatory proteins by the ubiquitin proteolytic pathway (UPP) is an established paradigm of cell cycle regulation during the G2/M and G1/S transitions. Less is known about roles for the UPP during S phase. Here we present evidence that dynamic cell cycle–dependent changes in levels of UbcH7 regulate entrance into and progression through S phase. In diverse cell lines, UbcH7 protein levels are dramatically reduced in S phase but are fully restored by G2. Knockdown of UbcH7 increases the proportion of cells in S phase and doubles the time to traverse S phase, whereas UbcH7 overexpression reduces the proportion of cells in S phase. These data suggest a role for UbcH7 targets in the completion of S phase and entry into G2. Notably, UbcH7 knockdown was coincident with elevated levels of the checkpoint kinase Chk1 but not Chk2. These results argue that UbcH7 promotes S phase progression to G2 by modulating the intra-S phase checkpoint mediated by Chk1. Furthermore, UbcH7 levels appear to be regulated by a UPP. Together the data identify novel roles for the UPP, specifically UbcH7 in the regulation of S phase transit time as well as in cell proliferation.

* Present address: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.

Address correspondence to: Allen Taylor (allen.taylor{at}tufts.edu)

Abbreviations used: APC/C, anaphase-promoting complex/cyclosome; ATR, ataxia telangiectasia and Rad3 related; CDK, cyclin-dependent kinase; HLE, human lens epithelial; HU, hydroxyurea; NS, nonspecific; PTEN, phosphate and tensin homolog deleted on chromosome 10; SCF, Skp1, Cul, F box complex; Ubc, ubiquitin-conjugating enzyme; UPP, ubiquitin proteasome pathway.