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

Cell Research
Zhiming LiWei-Guo Zhu

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.

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Citations

Feb 21, 2019·Nucleic Acids Research·Zhifeng WangXingzhi Xu
Jun 6, 2019·Critical Reviews in Biochemistry and Molecular Biology·Jae Jin KimKyle M Miller
Jan 24, 2020·Nucleic Acids Research·Tianyun HouWei-Guo Zhu
Aug 23, 2020·International Journal of Molecular Sciences·Marta AndrésAlicia Roque
Nov 11, 2020·Cells·Juliette FerrandSophie E Polo
Jan 6, 2021·Genes & Development·Laura Prendergast, Danny Reinberg
May 8, 2020·The Journal of Reproduction and Development·Daiki ShikataNaojiro Minami
Jun 16, 2021·Open Biology·Ming TangWei-Guo Zhu
Nov 6, 2021·Nature Communications·Fen YangMark T Bedford

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Methods Mentioned

BETA
acetylation
histone acetylation
pull-down
electrophoresis
Co-IP
co-immunoprecipitation
immunoprecipitation
PCR
transfection
PARylation

Software Mentioned

ImageJ
CASP ( Comet Assay Software Project

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