IKK and NF-kappa B-mediated regulation of Claspin impacts on ATR checkpoint function

Niall Steven Kenneth, Sharon Mudie, Sonia Rocha

    Research output: Contribution to journalArticlepeer-review

    30 Citations (Scopus)

    Abstract

    In response to replication stress, Claspin mediates the phosphorylation and activation of Chk1 by ATR. Claspin is not only necessary for the propagation of the DNA-damage signal, but its destruction by the ubiquitin-proteosome pathway is required to allow the cell to continue the cell cycle allowing checkpoint recovery. Here, we demonstrate that both the NF-kappa B family of transcription factors and their upstream kinase IKK can regulate Claspin levels by controlling its mRNA expression. Furthermore, we show that c-Rel directly controls Claspin gene transcription. Disruption of IKK and specific NF-kappa B members impairs ATR-mediated checkpoint function following DNA damage. Importantly, hyperactivation of IKK results in a failure to inactivate Chk1 and impairs the recovery from the DNA checkpoint. These results uncover a novel function for IKK and NF-kappa B modulating the DNA-damage checkpoint response, allowing the cell to integrate different signalling pathways with the DNA-damage response. The EMBO Journal (2010) 29, 2966-2978. doi: 10.1038/emboj.2010.171; Published online 23 July 2010

    Original languageEnglish
    Pages (from-to)2966-2978
    Number of pages13
    JournalEMBO Journal
    Volume29
    Issue number17
    DOIs
    Publication statusPublished - 1 Sept 2010

    Keywords

    • Chk1
    • Claspin
    • IKK
    • NF-kappa B
    • CELL-CYCLE
    • CHK1 ACTIVATION
    • GENE-EXPRESSION
    • BREAST-CANCER
    • DEGRADATION
    • RECOVERY
    • PHOSPHORYLATION
    • DOWNSTREAM
    • INHIBITION
    • PATHWAYS

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