Identification of the MMS22L-TONSL complex that promotes homologous recombination

Eris Duro, Cecilia Lundin, Katrine Ask, Luis Sanchez-Pulido, Thomas J. MacArtney, Rachel Toth, Chris P. Ponting, Anja Groth, Thomas Helleday, John Rouse (Lead / Corresponding author)

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    Abstract

    Budding yeast Mms22 is required for homologous recombination (HR)-mediated repair of stalled or broken DNA replication forks. Here we identify a human Mms22-like protein (MMS22L) and an MMS22L-interacting protein, NF kappa BIL2/TONSL. Depletion of MMS22L or TONSL from human cells causes a high level of double-strand breaks (DSBs) during DNA replication. Both proteins accumulate at stressed replication forks, and depletion of MMS22L or TONSL from cells causes hypersensitivity to agents that cause S phase-associated DSBs, such as topoisomerase (TOP) inhibitors. In this light, MMS22L and TONSL are required for the HR-mediated repair of replication fork-associated DSBs. In cells depleted of either protein, DSBs induced by the TOP1 inhibitor camptothecin are resected normally, but the loading of the RAD51 recombinase is defective. Therefore, MMS22L and TONSL are required for the maintenance of genome stability when unscheduled DSBs occur in the vicinity of DNA replication forks.

    Original languageEnglish
    Pages (from-to)632-644
    Number of pages13
    JournalMolecular Cell
    Volume40
    Issue number4
    DOIs
    Publication statusPublished - 24 Nov 2010

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