Division of Genome Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Prog Mol Biol Transl Sci. 2012;110:263-88. doi: 10.1016/B978-0-12-387665-2.00010-9.
The ataxia telangiectasia-mutated (ATM) protein kinase is the master regulator of the DNA double-strand break (DSB) repair pathway. The activation of ATM involves its recruitment to the DSB through interaction with the mre11-rad50-nbs1 complex, followed by the acetylation of ATM by the Tip60 acetyltransferase. This acetylation of ATM within its regulatory domain is essential for activating ATM's kinase activity. Further work has now revealed that Tip60 is activated through direct interaction between Tip60's chromodomain and histone H3 trimethylated on lysine 9 (H3K9me3). The loading of Tip60 onto the chromatin at DSBs therefore represents the primary mechanism for activation of Tip60's acetyltransferase activity in response to DNA damage. The ability of H3K9me3 at DSBs to regulate the activity of Tip60 and the subsequent activation of ATM emphasizes the crucial role played by chromatin architecture in regulating DSB repair. Further, histone methylation and chromatin structure are disrupted in human cancers, implying that altered chromatin structure in tumor cells may impact DSB repair, increasing genomic instability and contributing to the progression of cancer.
共济失调毛细血管扩张突变（ATM）蛋白激酶是 DNA 双链断裂（DSB）修复途径的主要调控因子。ATM 的激活涉及通过与 mre11-rad50-nbs1 复合物相互作用将其募集到 DSB，随后由 Tip60 乙酰转移酶对 ATM 进行乙酰化。ATM 在其调节域中的这种乙酰化对于激活 ATM 的激酶活性是必不可少的。进一步的工作现在表明，Tip60 通过 Tip60 的 chromodomain 与赖氨酸 9 上三甲基化的组蛋白 H3（H3K9me3）之间的直接相互作用而被激活。因此，Tip60 加载到 DSB 上的染色质代表了 Tip60 的乙酰转移酶活性对 DNA 损伤作出响应的主要激活机制。DSB 处的 H3K9me3 调节 Tip60 的活性以及随后的 ATM 激活，强调了染色质结构在调节 DSB 修复中的关键作用。此外，组蛋白甲基化和染色质结构在人类癌症中被破坏，这意味着肿瘤细胞中染色质结构的改变可能会影响 DSB 修复，增加基因组不稳定性并促进癌症的进展。
