Dormant Origins, the Licensing Checkpoint, and the Response to Replicative Stresses

Debbie McIntosh, J. Julian Blow

    Research output: Contribution to journalArticle

    67 Citations (Scopus)

    Abstract

    Only ~10% of replication origins that are licensed by loading minichromosome maintenance 2-7 (MCM2-7) complexes are normally used, with the majority remaining dormant. If replication fork progression is inhibited, nearby dormant origins initiate to ensure that all of the chromosomal DNA is replicated. At the same time, DNA damage-response kinases are activated, which preferentially suppress the assembly of new replication factories. This diverts initiation events away from completely new areas of the genome toward regions experiencing replicative stress. Mice hypomorphic for MCM2-7, which activate fewer dormant origins in response to replication inhibition, are cancer-prone and are genetically unstable. The licensing checkpoint delays entry into S phase if an insufficient number of origins have been licensed. In contrast, humans with Meier-Gorlin syndrome have mutations in pre-RC proteins and show defects in cell proliferation that may be a consequence of chronic activation of the licensing checkpoint.
    Original languageEnglish
    Article number012955
    Number of pages10
    JournalCold spring harbor perspectives in biology
    Volume4
    Issue number10
    DOIs
    Publication statusPublished - Oct 2012

    Keywords

    • FACTORY ACTIVATION
    • MEIER-GORLIN SYNDROME
    • PRIMORDIAL DWARFISM
    • TUMOR SUPPRESSION
    • MAMMALIAN-CELLS
    • EUKARYOTIC DNA-REPLICATION
    • S-PHASE CHECKPOINT
    • RECOGNITION COMPLEX
    • HUMAN-CELLS
    • XENOPUS EGG EXTRACTS

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