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

• Published in: Nature communications 2019-11, Vol.10 (1), p.5191-11, Article 5191
• Main Authors: Salguero, Israel, Belotserkovskaya, Rimma, Coates, Julia, Sczaniecka-Clift, Matylda, Demir, Mukerrem, Jhujh, Satpal, Wilson, Marcus D., Jackson, Stephen P.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/31; 14/19; 14/34; 14/63; 42/109; 42/35; 42/41; 42/44; 631/337; 631/80; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Motifs; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cell lines; Cell survival; Chromatin; Chromatin - genetics; Chromatin - metabolism; CRISPR; Damage tolerance; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Double-strand break repair; Genomes; Histone H2A; Histones; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Humans; Localization; multidisciplinary; Science; Science (multidisciplinary); Signal transduction; Tumor Suppressor p53-Binding Protein 1 - genetics; Tumor Suppressor p53-Binding Protein 1 - metabolism; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 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. MDC1 and H2AX interact and accumulate at sites of DNA damage, functioning to recruit additional factors involved in the repair process. Here the authors uncover a function for MDC1 that is independent of the presence of H2AX and is mediated through its PST-repeat region.