| Literature DB >> 24882211 |
Mu Zhang1, Shengyan Xiang1, Heui-Yun Joo2, Lei Wang1, Kendra A Williams1, Wei Liu1, Chen Hu1, Dan Tong3, Joshua Haakenson1, Chuangui Wang4, Shengping Zhang4, Ryan E Pavlovicz5, Amanda Jones2, Kristina H Schmidt6, Jinfu Tang1, Huiqin Dong1, Bin Shan7, Bin Fang8, Rangasudhagar Radhakrishnan9, Peter M Glazer10, Patrick Matthias11, John Koomen8, Edward Seto9, Gerold Bepler12, Santo V Nicosia13, Jiandong Chen9, Chenglong Li14, Liya Gu3, Guo-Min Li3, Wenlong Bai15, Hengbin Wang2, Xiaohong Zhang16.
Abstract
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.Entities:
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Year: 2014 PMID： 24882211 PMCID： PMC4188514 DOI： 10.1016/j.molcel.2014.04.028
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970