| Title | The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair |
| Authors | Qiu, Lingyu Xu, Wenchao Lu, Xiaopeng Chen, Feng Chen, Yongcan Tian, Yuan Zhu, Qian Liu, Xiangyu Wang, Yongqing Pei, Xin-Hai Xu, Xingzhi Zhang, Jun Zhu, Wei-Guo |
| Affiliation | Shenzhen Univ, Med Sch, Dept Biochem & Mol Biol, Int Canc Ctr,Guangdong Key Lab Genome Instabil & H, Shenzhen 518055, Peoples R China Univ Toledo, Med Ctr, Div Rheumatol & Immunol, 3120 Glendale Ave, Toledo, OH 43614 USA Shenzhen Univ, Med Sch, Guangdong Key Lab Genome Instabil & Human Dis Prev, Marshall Lab Biomed Engn,Dept Anat & Histol, Shenzhen, 518055, Peoples R China Shenzhen Univ, Med Sch, Dept Cell Biol & Med Genet, Int Canc Ctr,Guangdong Key Lab Genome Instabil & H, Shenzhen 518055, Peoples R China Wannan Med Coll, Sch Basic Med Sci, Wuhu 241002, Anhui, Peoples R China Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biochem & Biophys, Beijing 100191, Peoples R China |
| Keywords | DNA-DAMAGE RESPONSE HISTONE UBIQUITINATION RNF168 UBIQUITYLATION 53BP1 RNF8 H2AX PHOSPHORYLATION POLYUBIQUITIN ACETYLATION |
| Issue Date | 2023 |
| Publisher | NUCLEIC ACIDS RESEARCH |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/689152 |
| ISSN | 0305-1048 |
| DOI | 10.1093/nar/gkad631 |
| Indexed | SCI(E) |
| Appears in Collections: | 医学部待认领 |
