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

Israel Salguero, Rimma Belotserkovskaya, Julia Coates, Matylda Sczaniecka-Clift, Mukerrem Demir, Satpal Jhujh, Marcus D. Wilson and Stephen P. Jackson ()
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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
Marcus D. Wilson: University of Edinburgh, Michael Swann Building
Stephen P. Jackson: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12929-5

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