Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair

Cell Res. 2018 Jul;28(7):756-770. doi: 10.1038/s41422-018-0048-0. Epub 2018 May 29.

Abstract

Linker histone H1 is a master regulator of higher order chromatin structure, but its involvement in the DNA damage response and repair is unclear. Here, we report that linker histone H1.2 is an essential regulator of ataxia telangiectasia mutated (ATM) activation. We show that H1.2 protects chromatin from aberrant ATM activation through direct interaction with the ATM HEAT repeat domain and inhibition of MRE11-RAD50-NBS1 (MRN) complex-dependent ATM recruitment. Upon DNA damage, H1.2 undergoes rapid PARP1-dependent chromatin dissociation through poly-ADP-ribosylation (PARylation) of its C terminus and further proteasomal degradation. Inhibition of H1.2 displacement by PARP1 depletion or an H1.2 PARylation-dead mutation compromises ATM activation and DNA damage repair, thus leading to impaired cell survival. Taken together, our findings suggest that linker histone H1.2 functions as a physiological barrier for ATM to target the chromatin, and PARylation-mediated active H1.2 turnover is required for robust ATM activation and DNA damage repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Survival
  • Chromatin / genetics*
  • DNA Damage
  • DNA Repair Enzymes / metabolism
  • DNA Repair*
  • DNA-Binding Proteins / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Histones / physiology*
  • Humans
  • MRE11 Homologue Protein / metabolism
  • Mutation
  • Nuclear Proteins / metabolism
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Poly ADP Ribosylation

Substances

  • Cell Cycle Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • MRE11 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, human
  • DNA Repair Enzymes