Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Martin R. Higgs, Koichi Sato, John J. Reynolds, Shabana Begum, Rachel Bayley, Amalia Goula, Audrey Vernet, Karissa L. Paquin, David G. Skalnik, Wataru Kobayashi, Minoru Takata, Niall G. Howlett, Hitoshi Kurumizaka, Hiroshi Kimura, Grant S. Stewart

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.

    Original languageEnglish
    Pages (from-to)25-41.e6
    JournalMolecular Cell
    Volume71
    Issue number1
    DOIs
    Publication statusPublished - 2018 Jul 5

    Keywords

    • BOD1L
    • FANCD2
    • histone methylation
    • lysine methyltransferase
    • replication fork replication
    • replication stress
    • SETD1A

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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  • Cite this

    Higgs, M. R., Sato, K., Reynolds, J. J., Begum, S., Bayley, R., Goula, A., Vernet, A., Paquin, K. L., Skalnik, D. G., Kobayashi, W., Takata, M., Howlett, N. G., Kurumizaka, H., Kimura, H., & Stewart, G. S. (2018). Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2. Molecular Cell, 71(1), 25-41.e6. https://doi.org/10.1016/j.molcel.2018.05.018