Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair.
Cell Res
; 28(7): 756-770, 2018 07.
Article
in En
| MEDLINE
| ID: mdl-29844578
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chromatin
/
Histones
/
DNA Repair
/
Ataxia Telangiectasia Mutated Proteins
/
Poly (ADP-Ribose) Polymerase-1
Limits:
Humans
Language:
En
Journal:
Cell Res
Year:
2018
Document type:
Article