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, Stephen P. Jackson

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article number5191
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 15 Nov 2019

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