From the Karmanos Cancer Institute, Molecular Therapeutics Program, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201.
the Karmanos Cancer Institute, Cancer Biology Graduate Program, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201.
J Biol Chem. 2019 Apr 12;294(15):5813-5826. doi: 10.1074/jbc.RA118.006374. Epub 2019 Feb 15.
MutL homolog 1 (MLH1) is a key DNA mismatch repair protein, which plays an important role in maintenance of genomic stability and the DNA damage response. Here, we report that MLH1 is a novel substrate of histone deacetylase 6 (HDAC6). HDAC6 interacts with and deacetylates MLH1 both and Interestingly, deacetylation of MLH1 blocks the assembly of the MutSα-MutLα complex. Moreover, we have identified four novel acetylation sites in MLH1 by MS analysis. The deacetylation mimetic mutant, but not the WT and the acetylation mimetic mutant, of MLH1 confers resistance to 6-thioguanine. Overall, our findings suggest that the MutSα-MutLα complex serves as a sensor for DNA damage response and that HDAC6 disrupts the MutSα-MutLα complex by deacetylation of MLH1, leading to the tolerance of DNA damage.
MutL 同源物 1（MLH1）是一种关键的 DNA 错配修复蛋白，在维持基因组稳定性和 DNA 损伤反应中发挥重要作用。在这里，我们报告 MLH1 是组蛋白去乙酰化酶 6（HDAC6）的一个新底物。HDAC6 与 MLH1 相互作用并使其去乙酰化。有趣的是，MLH1 的去乙酰化阻止了 MutSα-MutLα 复合物的组装。此外，我们通过 MS 分析鉴定了 MLH1 中的四个新的乙酰化位点。去乙酰化模拟突变体，但不是 WT 和乙酰化模拟突变体，赋予了对 6-硫鸟嘌呤的抗性。总的来说，我们的发现表明 MutSα-MutLα 复合物作为 DNA 损伤反应的传感器，而 HDAC6 通过去乙酰化 MLH1 破坏 MutSα-MutLα 复合物，导致对 DNA 损伤的耐受性。
