The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair-Reference-Cited by-同舟云学术

The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair

Published:2023-07-28 Issue:17 Volume:51 Page:9166-9182
ISSN:0305-1048
Container-title:Nucleic Acids Research
language:en
Short-container-title:

Author:

Qiu Lingyu¹,Xu Wenchao¹,Lu Xiaopeng¹,Chen Feng¹,Chen Yongcan¹,Tian Yuan¹,Zhu Qian¹,Liu Xiangyu¹,Wang Yongqing²,Pei Xin-Hai³,Xu Xingzhi⁴^ORCID,Zhang Jun¹,Zhu Wei-Guo¹⁵⁶^ORCID

Affiliation:

1. International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School , Shenzhen 518055, China

2. Division of Rheumatology and Immunology, University of Toledo Medical Center , 3120 Glendale Avenue, Toledo 43614, OH , USA

3. Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Anatomy and Histology, Shenzhen University Medical School , Shenzhen 518055, China

4. International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Cell Biology and Medical Genetics, Shenzhen University Medical School , Shenzhen 518055, China

5. School of Basic Medical Sciences , Wannan Medical College, Wuhu, Anhui 241002, China

6. Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191, China

Abstract

Abstract Histone deacetylase 6 (HDAC6) mediates DNA damage signaling by regulating the mismatch repair and nucleotide excision repair pathways. Whether HDAC6 also mediates DNA double-strand break (DSB) repair is unclear. Here, we report that HDAC6 negatively regulates DSB repair in an enzyme activity-independent manner. In unstressed cells, HDAC6 interacts with H2A/H2A.X to prevent its interaction with the E3 ligase RNF168. Upon sensing DSBs, RNF168 rapidly ubiquitinates HDAC6 at lysine 116, leading to HDAC6 proteasomal degradation and a restored interaction between RNF168 and H2A/H2A.X. H2A/H2A.X is ubiquitinated by RNF168, precipitating the recruitment of DSB repair factors (including 53BP1 and BRCA1) to chromatin and subsequent DNA repair. These findings reveal novel regulatory machinery based on an HDAC6–RNF168 axis that regulates the H2A/H2A.X ubiquitination status. Interfering with this axis might be leveraged to disrupt a key mechanism of cancer cell resistance to genotoxic damage and form a potential therapeutic strategy for cancer.

Funder

National Natural Science Foundation of China

Science and Technology Program of Guangdong

Guangdong Basic and Applied Basic Research Foundation

Shenzhen Municipal Commission of Science and Technology Innovation

Shenzhen University 2035 Program for Excellent Research

Publisher

Oxford University Press (OUP)

Subject

Genetics

Link

https://academic.oup.com/nar/article-pdf/51/17/9166/51719919/gkad631.pdf