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MBC in Press, published online ahead of print August 15, 2007
Mol. Biol. Cell 10.1091/mbc.E06-12-1148

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Submitted on December 26, 2006
Revised on June 25, 2007
Accepted on August 3, 2007

Human Mcm10 Regulates the Catalytic Subunit of DNA Polymerase-{alpha} and Prevents DNA Damage During Replication

Sharbani Chattopadhyay and Anja-Katrin Bielinsky

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455

Monitoring Editor: Daniel Lew

In S. cerevisiae, minichromosome maintenance protein (Mcm) 10 interacts with pol-{alpha} and functions as a nuclear chaperone for the catalytic subunit, which is rapidly degraded in the absence of Mcm10. We report here that the interaction between Mcm10 and pol-{alpha} is conserved in human cells. We utilized a siRNA-based approach to deplete Mcm10 in HeLa cells and observed that the catalytic subunit of pol-{alpha}, p180, was degraded with similar kinetics as Mcm10, whereas the regulatory pol-{alpha} subunit, p68, remained unaffected. Simultaneous loss of Mcm10 and p180 inhibited S phase entry and led to an accumulation of already replicating cells in late S/G2 as a result of DNA damage, which triggered apoptosis in a subpopulation of cells. These phenotypes differed considerably from analogous studies in Drosophila embryo cells that did not exhibit a similar arrest. To further dissect the roles of Mcm10 and p180 in human cells, we depleted p180 alone and observed a significant delay in S phase entry and fork progression but little effect on cell viability. These results argue that cells can tolerate low levels of p180 as long as Mcm10 is present to "recycle" it. Thus, human Mcm10 regulates both replication initiation and elongation and maintains genome integrity.

Address correspondence to: Anja-Katrin Bielinsky (bieli003{at}umn.edu)




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