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.
Division of Rheumatology and Immunology, University of Toledo Medical Center, 3120 Glendale Avenue, Toledo 43614, OH, USA.
Nucleic Acids Res. 2023 Sep 22;51(17):9166-9182. doi: 10.1093/nar/gkad631.
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.
组蛋白去乙酰化酶 6（HDAC6）通过调节错配修复和核苷酸切除修复途径来介导 DNA 损伤信号转导。HDAC6 是否也介导 DNA 双链断裂（DSB）修复尚不清楚。在这里，我们报告 HDAC6 以酶活性非依赖性的方式负调控 DSB 修复。在未受应激的细胞中，HDAC6 与 H2A/H2A.X 相互作用，以防止其与 E3 连接酶 RNF168 相互作用。在感知到 DSB 后，RNF168 迅速在赖氨酸 116 处泛素化 HDAC6，导致 HDAC6 蛋白酶体降解，并恢复 RNF168 与 H2A/H2A.X 的相互作用。H2A/H2A.X 被 RNF168 泛素化，促使 DSB 修复因子（包括 53BP1 和 BRCA1）募集到染色质上，随后进行 DNA 修复。这些发现揭示了基于 HDAC6-RNF168 轴的新型调控机制，该机制调节 H2A/H2A.X 的泛素化状态。干扰这个轴可能被用来破坏癌细胞对遗传毒性损伤的抵抗的关键机制，并为癌症形成一种潜在的治疗策略。
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