Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re-replication in Xenopus

Anatoliy Li, J. Julian Blow

    Research output: Contribution to journalArticle

    109 Citations (Scopus)

    Abstract

    In late mitosis and G1, Mcm2–7 are assembled onto replication origins to 'license' them for initiation. At other cell cycle stages, licensing is inhibited, thus ensuring that origins fire only once per cell cycle. Three additional factors—the origin recognition complex, Cdc6 and Cdt1—are required for origin licensing. We examine here how licensing is regulated in Xenopus egg extracts. We show that Cdt1 is downregulated late in the cell cycle by two different mechanisms: proteolysis, which occurs in part due to the activity of the anaphase-promoting complex (APC/C), and inhibition by a protein called geminin. If both these regulatory mechanisms are abrogated, extracts undergo uncontrolled re-licensing and re-replication. The extent of re-replication is limited by checkpoint kinases that are activated as a consequence of re-replication itself. These results allow us to build a comprehensive model of how re-replication of DNA is prevented in Xenopus, with Cdt1 regulation being the key feature. The results also explain the original experiments that led to the proposal of a replication licensing factor.
    Original languageEnglish
    Pages (from-to)395-404
    Number of pages10
    JournalThe EMBO Journal
    Volume24
    Issue number2
    DOIs
    Publication statusPublished - Jan 2005

    Keywords

    • Cdt1
    • DNA replication
    • Geminin
    • Replication licensing
    • Xenopus

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