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A. Taylor, E. Whitcomb, E. Dudek, Q. Liu; A Role for Ubch7 in the Regulation of S Phase of the Cell Cycle. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3258.
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© ARVO (1962-2015); The Authors (2016-present)
Timely degradation of cell cycle regulatory proteins by the ubiquitin dependent proteolytic pathway (UPP) is an established paradigm of cell cycle regulation during the G2/M and G1/S transitions. Far less is known about the rules for UPP regulation during S phase. Here we present novel evidence that dynamic cell-cycle dependent regulation of levels of the ubiquitin-conjugating enzyme (Ubc) H7, regulates both entrance into S phase as well as timely progression through S phase to G2.
We used human lens and HeLa cell lines, RNAi to suppress UbcH7 and FAX analyses to monitor cell cycle.
We showed that 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 decreases the proportion in G1. Consistently, UbcH7 over expression reduces the proportion of S phase cells while increasing the proportion of G1 cells. UbcH7 depletion doubles the time to complete S phase in synchronized cells, suggesting a role for UbcH7 targets in the completion of S phase and entry into G2. Notably, these effects of UbcH7 knockdown were coincident with elevated levels of the checkpoint kinase Chk1 and P-280 Chk1 (but not Chk2) and with attenuated levels of phosphorylated PTEN. 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 post-translational mechanisms involving the UPP.
Together these data identify UbcH7 as a regulator of S phase entry and progression and suggest a new role for UbcH7 and the UPP in cell proliferation in health and disease.
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