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15.11.19 MDC1 retains capacity to recruit repair factors to sites of DNA damage in absence of H2AX

last modified Nov 15, 2019 10:08 AM
Salguero et al. from Steve Jackson's lab show that DNA-damage response protein MDC1 unexpectedly retains its capacity to recruit repair factors to sites of damage in the absence of H2AX. This represents an alternative pathway to promote DNA repair.
15.11.19 MDC1 retains capacity to recruit repair factors to sites of DNA damage in absence of H2AX

Human cells treated with a DNA-damaging agent and stained for 53BP1 (green) and cyclin A (red)

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

Salguero I et al. (2019) Nat Commun 10, 5191. DOI: 10.1038/s41467-019-12929-5

 

Abstract from the paper

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.

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