Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress

Anna M Woodward, Thomas Göhler, M Gloria Luciani, Maren Oehlmann, Xinquan Ge, Anton Gartner, Dean A Jackson, J Julian Blow

    Research output: Contribution to journalArticle

    229 Citations (Scopus)

    Abstract

    In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of the excess Mcm2-7 is unknown. Using Xenopus laevis egg extracts, we show that these excess Mcm2-7 complexes license additional dormant origins that do not fire during unperturbed S phases because of suppression by a caffeine-sensitive checkpoint pathway. Use of these additional origins can allow complete genome replication in the presence of replication inhibitors. These results suggest that metazoan replication origins are actually comprised of several candidate origins, most of which normally remain dormant unless cells experience replicative stress. Consistent with this model, using Caenorhabditis elegans, we show that partial RNAi-based knockdown of MCMs that has no observable effect under normal conditions causes lethality upon treatment with low, otherwise nontoxic, levels of the replication inhibitor hydroxyurea.
    Original languageEnglish
    Pages (from-to)673-83
    Number of pages11
    JournalJournal of Cell Biology
    Volume173
    Issue number5
    DOIs
    Publication statusPublished - 2006

    Fingerprint

    Minichromosome Maintenance Proteins
    Replication Origin
    Licensure
    S Phase
    Hydroxyurea
    Caenorhabditis elegans
    Xenopus laevis
    RNA Interference
    Caffeine
    Mitosis
    Ovum
    Genome
    DNA

    Cite this

    Woodward, Anna M ; Göhler, Thomas ; Luciani, M Gloria ; Oehlmann, Maren ; Ge, Xinquan ; Gartner, Anton ; Jackson, Dean A ; Blow, J Julian. / Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. In: Journal of Cell Biology. 2006 ; Vol. 173, No. 5. pp. 673-83.
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    abstract = "In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of the excess Mcm2-7 is unknown. Using Xenopus laevis egg extracts, we show that these excess Mcm2-7 complexes license additional dormant origins that do not fire during unperturbed S phases because of suppression by a caffeine-sensitive checkpoint pathway. Use of these additional origins can allow complete genome replication in the presence of replication inhibitors. These results suggest that metazoan replication origins are actually comprised of several candidate origins, most of which normally remain dormant unless cells experience replicative stress. Consistent with this model, using Caenorhabditis elegans, we show that partial RNAi-based knockdown of MCMs that has no observable effect under normal conditions causes lethality upon treatment with low, otherwise nontoxic, levels of the replication inhibitor hydroxyurea.",
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    Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. / Woodward, Anna M; Göhler, Thomas; Luciani, M Gloria; Oehlmann, Maren; Ge, Xinquan; Gartner, Anton; Jackson, Dean A; Blow, J Julian.

    In: Journal of Cell Biology, Vol. 173, No. 5, 2006, p. 673-83.

    Research output: Contribution to journalArticle

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    AU - Göhler, Thomas

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    AU - Ge, Xinquan

    AU - Gartner, Anton

    AU - Jackson, Dean A

    AU - Blow, J Julian

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    AB - In late mitosis and early G1, replication origins are licensed for subsequent use by loading complexes of the minichromosome maintenance proteins 2-7 (Mcm2-7). The number of Mcm2-7 complexes loaded onto DNA greatly exceeds the number of replication origins used during S phase, but the function of the excess Mcm2-7 is unknown. Using Xenopus laevis egg extracts, we show that these excess Mcm2-7 complexes license additional dormant origins that do not fire during unperturbed S phases because of suppression by a caffeine-sensitive checkpoint pathway. Use of these additional origins can allow complete genome replication in the presence of replication inhibitors. These results suggest that metazoan replication origins are actually comprised of several candidate origins, most of which normally remain dormant unless cells experience replicative stress. Consistent with this model, using Caenorhabditis elegans, we show that partial RNAi-based knockdown of MCMs that has no observable effect under normal conditions causes lethality upon treatment with low, otherwise nontoxic, levels of the replication inhibitor hydroxyurea.

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