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

Nat Commun. 2019 Nov 15;10(1):5191. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA Repair
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / metabolism


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Chromatin
  • H2AX protein, human
  • Histones
  • MDC1 protein, human
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1