mdc1 pst repeat region promotes histone h2ax independent chromatin association and dna damage tolerance

• DOI: 10.17863/cam.44719
• Publication Date: 2019-11-15
• Authors: Julia Coates; Satpal Jhujh; Satpal Jhujh; Stephen P. Jackson; Matylda Sczanieck...; Israel Salguero; Marcus D. Wilson; Rimma Belotserkov...; Mukerrem Demir
• Keywords: 0301 basic medicine; DNA Repair; Science; Amino Acid Motifs; /42/109; Cell Cycle Proteins; /13/106; /13/109; Article; Cell Line; Histones; 03 medical and health sciences; /14/34; /42/44; /42/41; Humans; DNA Breaks, Double-Stranded; /14/19; Adaptor Proteins, Signal Transducing; 0303 health sciences; Q; article; Chromatin; /13/31; /42/35; /14/63; /631/80; Tumor Suppressor p53-Binding Protein 1; /631/337; DNA Damage

AbstractHistone 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.