Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress

Xin Quan Ge, Dean A. Jackson, J. Julian Blow

    Research output: Contribution to journalArticlepeer-review


    In late mitosis and early G1, Mcm2-7 complexes are loaded onto DNA to license replication origins for use in the upcoming S phase. However, the amount of Mcm2-7 loaded is in significant excess over the number of origins normally used. We show here that in human cells, excess chromatin-bound Mcm2-7 license dormant replication origins that do not fire during normal DNA replication, in part due to checkpoint activity. Dormant origins were activated within active replicon clusters if replication fork progression was inhibited, despite the activation of S-phase checkpoints. After lowering levels of chromatin-bound Mcm2-7 in human cells by RNA interference (RNAi), the use of dormant origins was suppressed in response to replicative stress. Although cells with lowered chromatin-bound Mcm2-7 replicated at normal rates, when challenged with replication inhibitors they had dramatically reduced rates of DNA synthesis and reduced viability. These results suggest that the use of dormant origins licensed by excess Mcm2-7 is a new and physiologically important mechanism that cells utilize to maintain DNA replication rates under conditions of replicative stress. We propose that checkpoint kinase activity can preferentially suppress initiation within inactive replicon clusters, thereby directing new initiation events toward active clusters that are experiencing replication problems. © 2007 by Cold Spring Harbor Laboratory Press.
    Original languageEnglish
    Pages (from-to)3331-3341
    Number of pages10
    JournalGenes and development
    Issue number24
    Publication statusPublished - 15 Dec 2007


    • Dormant origins
    • Genetic stability
    • Mcm2-7
    • Replication origins


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