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MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance

Author

Listed:
  • Israel Salguero

    (University of Cambridge)

  • Rimma Belotserkovskaya

    (University of Cambridge)

  • Julia Coates

    (University of Cambridge)

  • Matylda Sczaniecka-Clift

    (University of Cambridge)

  • Mukerrem Demir

    (University of Cambridge)

  • Satpal Jhujh

    (University of Cambridge
    University of Birmingham, Edgbaston)

  • Marcus D. Wilson

    (University of Edinburgh, Michael Swann Building)

  • Stephen P. Jackson

    (University of Cambridge)

Abstract

Histone H2AX and MDC1 are key DNA repair and DNA-damage signalling proteins. When DNA double-strand breaks (DSBs) occur, H2AX is phosphorylated and then recruits MDC1, which in turn serves as a docking platform to promote the localization of other factors, including 53BP1, to DSB sites. Here, by using CRISPR-Cas9 engineered human cell lines, we identify a hitherto unknown, H2AX-independent, function of MDC1 mediated by its PST-repeat region. We show that the PST-repeat region directly interacts with chromatin via the nucleosome acidic patch and mediates DNA damage-independent association of MDC1 with chromatin. We find that this region is largely functionally dispensable when the canonical γH2AX-MDC1 pathway is operative but becomes critical for 53BP1 recruitment to DNA-damage sites and cell survival following DSB induction when H2AX is not available. Consequently, our results suggest a role for MDC1 in activating the DDR in areas of the genome lacking or depleted of H2AX.

Suggested Citation

  • Israel Salguero & Rimma Belotserkovskaya & Julia Coates & Matylda Sczaniecka-Clift & Mukerrem Demir & Satpal Jhujh & Marcus D. Wilson & Stephen P. Jackson, 2019. "MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12929-5
    DOI: 10.1038/s41467-019-12929-5
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    Cited by:

    1. Emilien Nicolas & Paul Simion & Marc Guérineau & Matthieu Terwagne & Mathilde Colinet & Julie Virgo & Maxime Lingurski & Anaïs Boutsen & Marc Dieu & Bernard Hallet & Karine Doninck, 2023. "Horizontal acquisition of a DNA ligase improves DNA damage tolerance in eukaryotes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Jessica L. Kelliher & Melissa L. Folkerts & Kaiyuan V. Shen & Wan Song & Kyle Tengler & Clara M. Stiefel & Seong-Ok Lee & Eloise Dray & Weixing Zhao & Brian Koss & Nicholas R. Pannunzio & Justin W. Le, 2024. "Evolved histone tail regulates 53BP1 recruitment at damaged chromatin," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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