MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance.
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Salguero, I., Belotserkovskaya, R., Coates, J., Sczaniecka-Clift, M., Demir, M., Jhujh, S., Wilson, M. D., & et al. (2019). MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance.. Nature communications, 10 (1), 5191. https://doi.org/10.1038/s41467-019-12929-5
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.
Cell Line, Chromatin, Humans, DNA Damage, Adaptor Proteins, Signal Transducing, Cell Cycle Proteins, Histones, DNA Repair, Amino Acid Motifs, DNA Breaks, Double-Stranded, Tumor Suppressor p53-Binding Protein 1
Research in the S.P.J. laboratory is funded by Cancer Research UK (programme grant C6/A18796) and Wellcome Investigator Award (206388/Z/17/Z). Institute core infrastructure funding is provided by Cancer Research UK (C6946/A24843) and Wellcome (WT203144). S.P.J. receives salary from the University of Cambridge. This work was funded by Cancer Research UK programme grant C6/A18796 (I.S.C., R.B., J.C., M.S-C. and M.D.), Wellcome Strategic Award 101126/Z/13/Z (I.S.C.) and ERC Advanced Research Grant DDREAM (M.S-C., M.D. and S.J.). MDW’s work is supported by Wellcome Trust (210493) and the University of Edinburgh. The Wellcome Centre for Cell Biology is supported by core funding from Wellcome Trust .
European Research Council (268536)
Cancer Research UK (18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (11224)
Wellcome Trust (101126/Z/13/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
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External DOI: https://doi.org/10.1038/s41467-019-12929-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297665
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