Human Geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis

AUTOR(ES)

Ballabeni, Andrea

FONTE

Nature Publishing Group

RESUMO

Geminin is an unstable inhibitor of DNA replication that negatively regulates the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation in Xenopus egg extracts. Here we describe a novel function of Geminin. We demonstrate that human Geminin protects CDT1 from proteasome-mediated degradation by inhibiting its ubiquitination. In particular, Geminin ensures basal levels of CDT1 during S phase and its accumulation during mitosis. Consistently, inhibition of Geminin synthesis during M phase leads to impairment of pre-RC formation and DNA replication during the following cell cycle. Moreover, we show that inhibition of CDK1 during mitosis, and not Geminin depletion, is sufficient for premature formation of pre-RCs, indicating that CDK activity is the major mitotic inhibitor of licensing in human cells. Taken together with recent data from our laboratory, our results demonstrate that Geminin is both a negative and positive regulator of pre-RC formation in human cells, playing a positive role in allowing CDT1 accumulation in G2–M, and preventing relicensing of origins in S–G2.

Documentos Relacionados

• Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re-replication in Xenopus
• Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation
• The B2 element of the Saccharomyces cerevisiae ARS1 origin of replication requires specific sequences to facilitate pre-RC formation
• Geminin Stabilizes Cdt1 during Meiosis in Xenopus Oocytes*
• Regulation of CDC6, Geminin, and CDT1 in Human Cells that Undergo Polyploidization