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

被引：12
|
作者：
Qiu, Lingyu [1 ]
Xu, Wenchao [1 ]
Lu, Xiaopeng [1 ]
Chen, Feng [1 ]
Chen, Yongcan [1 ]
Tian, Yuan [1 ]
Zhu, Qian [1 ]
Liu, Xiangyu [1 ]
Wang, Yongqing [2 ]
Pei, Xin-Hai [3 ]
Xu, Xingzhi [4 ]
Zhang, Jun [1 ]
Zhu, Wei-Guo [1 ,5 ,6 ]
机构：
[1] Shenzhen Univ, Med Sch, Dept Biochem & Mol Biol, Int Canc Ctr,Guangdong Key Lab Genome Instabil &, Shenzhen 518055, Peoples R China
[2] Univ Toledo, Med Ctr, Div Rheumatol & Immunol, 3120 Glendale Ave, Toledo, OH 43614 USA
[3] Shenzhen Univ, Med Sch, Guangdong Key Lab Genome Instabil & Human Dis Pre, Marshall Lab Biomed Engn,Dept Anat & Histol, Shenzhen, 518055, Peoples R China
[4] Shenzhen Univ, Med Sch, Dept Cell Biol & Med Genet, Int Canc Ctr,Guangdong Key Lab Genome Instabil &, Shenzhen 518055, Peoples R China
[5] Wannan Med Coll, Sch Basic Med Sci, Wuhu 241002, Anhui, Peoples R China
[6] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biochem & Biophys, Beijing 100191, Peoples R China
来源：
NUCLEIC ACIDS RESEARCH | 2023年 / 51卷 / 17期
基金：
中国国家自然科学基金;
关键词：
DNA-DAMAGE RESPONSE; HISTONE UBIQUITINATION; RNF168; UBIQUITYLATION; 53BP1; RNF8; H2AX; PHOSPHORYLATION; POLYUBIQUITIN; ACETYLATION;
D O I：
10.1093/nar/gkad631
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
引用
收藏
页码：9166 / 9182
页数：17
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