A PARP1-BRG1-SIRT1 axis promotes HR repair by reducing nucleosome density at DNA damage sites

Yu Chen; Haiping Zhang; Zhu Xu; Huanyin Tang; Anke Geng; Bailian Cai; Tao Su; Jiejun Shi; Cizhong Jiang; Xiao Tian; Andrei Seluanov; Jun Huang; Xiaoping Wan; Ying Jiang; Vera Gorbunova; Zhiyong Mao

doi:10.1093/nar/gkz592

A PARP1-BRG1-SIRT1 axis promotes HR repair by reducing nucleosome density at DNA damage sites

Nucleic Acids Res. 2019 Sep 19;47(16):8563-8580. doi: 10.1093/nar/gkz592.

Authors

Yu Chen¹, Haiping Zhang¹, Zhu Xu¹, Huanyin Tang¹, Anke Geng¹, Bailian Cai¹, Tao Su¹, Jiejun Shi¹, Cizhong Jiang¹, Xiao Tian², Andrei Seluanov², Jun Huang³, Xiaoping Wan¹, Ying Jiang¹, Vera Gorbunova², Zhiyong Mao¹

Affiliations

¹ Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
² Department of Biology, University of Rochester, Rochester, NY 14627, USA.
³ Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.

Abstract

Creating access to DNA double-strand break (DSB) sites in the chromatin context is an essential step during the repair process, but much remains to be determined about its regulatory mechanisms. Here, using a novel reporter cassette for simultaneous detection of homologous recombination (HR) and nonhomologous end joining (NHEJ) at the same chromosomal site, we report that the efficiency of HR but not NHEJ negatively correlates with nucleosome density. We demonstrate that PARP1 is required for HR by modulating nucleosome density at damage sites. Mechanistic studies indicate that the ATPase domain of BRG1 and the ZnF domain of SIRT1 interact with poly-ADP ribose (PAR) in response to DNA damage, and are responsible for bringing the two factors to broken DNA ends. At DNA damage sites, BRG1 and SIRT1 physically interact, whereupon SIRT1 deacetylates BRG1 at lysine residues 1029 and 1033, stimulating its ATPase activity to remodel chromatin and promote HR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Line
Cell Line, Tumor
Chloroquine / pharmacology
DNA / genetics*
DNA / metabolism
DNA Breaks, Double-Stranded
DNA End-Joining Repair
DNA Helicases / genetics*
DNA Helicases / metabolism
Fibroblasts / cytology
Fibroblasts / drug effects
Fibroblasts / metabolism
Gene Expression Regulation
Genes, Reporter
HEK293 Cells
Hepatocytes / cytology
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Nucleosomes / chemistry
Nucleosomes / drug effects
Nucleosomes / metabolism*
Phenanthrenes / pharmacology
Phthalazines / pharmacology
Piperazines / pharmacology
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / genetics*
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly Adenosine Diphosphate Ribose / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Protein Binding
Protein Interaction Domains and Motifs
Recombinational DNA Repair*
Sirtuin 1 / genetics*
Sirtuin 1 / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Nuclear Proteins
Nucleosomes
Phenanthrenes
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Transcription Factors
Poly Adenosine Diphosphate Ribose
Chloroquine
DNA
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
SIRT1 protein, human
Sirtuin 1
SMARCA4 protein, human
DNA Helicases
olaparib

Abstract

Publication types

MeSH terms

Substances

Grants and funding