HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα.
HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα.
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DOI：
10.1016/j.molcel.2014.04.028
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发表时间：
2014-07-03
期刊：
影响因子：
16
通讯作者：
Zhang, Xiaohong
中科院分区：
文献类型：
--
作者：
Zhang, Mu;Xiang, Shengyan;Joo, Heui-Yun;Wang, Lei;Williams, Kendra A.;Liu, Wei;Hu, Chen;Tong, Dan;Haakenson, Joshua;Wang, Chuangui;Zhang, Shengping;Pavlovicz, Ryan E.;Jones, Amanda;Schmidt, Kristina H.;Tang, Jinfu;Dong, Huiqin;Shan, Bin;Fang, Bin;Radhakrishnan, Rangasudhagar;Glazer, Peter M.;Matthias, Patrick;Koomen, John;Seto, Edward;Bepler, Gerold;Nicosia, Santo V.;Chen, Jiandong;Li, Chenglong;Gu, Liya;Li, Guo-Min;Bai, Wenlong;Wang, Hengbin;Zhang, Xiaohong
MutS 蛋白同源物 2 (MSH2) 是一种关键的 DNA 错配修复蛋白。它形成 MSH2-MSH6 (MutSα) 和 MSH2-MSH3 (MutSβ) 异二聚体，有助于确保基因组完整性。 MutSα 不仅可以识别和修复不匹配的核苷酸，还可以识别 DNA 损伤剂诱导的 DNA 加合物，并触发细胞周期停滞和细胞凋亡。细胞中 MutSα 的丢失或耗尽会导致微卫星不稳定 (MSI) 和对 DNA 损伤的抵抗力。尽管泛素-蛋白酶体途径可以降低 MutSα 的水平，但这种调节的详细机制仍然难以捉摸。在此，我们报道组蛋白脱乙酰酶 6 (HDAC6) 依次使 MSH2 脱乙酰化并泛素化，从而导致 MSH2 降解。此外，HDAC6 显着降低细胞对 DNA 损伤剂的敏感性，并通过下调 MSH2 降低细胞 DNA 错配修复活性。总的来说，这些发现揭示了维持适当水平的 MutSα 的机制。
MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutSα) and MSH2-MSH3 (MutSβ) heterodimers, which help to ensure genomic integrity. MutSα not only recognizes and repairs mismatched nucleotides but also recognizes DNA adducts induced by DNA-damaging agents, and triggers cell-cycle arrest and apoptosis. Loss or depletion of MutSα from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutSα can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Here we report that histone deacetylase 6 (HDAC6) sequentially deacetylates and ubiquitinates MSH2, leading to MSH2 degradation. In addition, HDAC6 significantly reduces cellular sensitivity to DNA-damaging agents and decreases cellular DNA mismatch repair activities by downregulation of MSH2. Overall, these findings reveal a mechanism by which proper levels of MutSα are maintained.
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