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PMID:24882211

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Citation

Zhang, M, Xiang, S, Joo, HY, Wang, L, Williams, KA, Liu, W, Hu, C, Tong, D, Haakenson, J, Wang, C, Zhang, S, Pavlovicz, RE, Jones, A, Schmidt, KH, Tang, J, Dong, H, Shan, B, Fang, B, Radhakrishnan, R, Glazer, PM, Matthias, P, Koomen, J, Seto, E, Bepler, G, Nicosia, SV, Chen, J, Li, C, Gu, L, Li, GM, Bai, W, Wang, H and Zhang, X (2014) HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Mol. Cell 55:31-46

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.

Links

PubMed PMC4188514 Online version:10.1016/j.molcel.2014.04.028

Keywords

Acetylation; Animals; Cells, Cultured; HEK293 Cells; HeLa Cells; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Histone Deacetylases/physiology; Humans; Mice; MutS Homolog 2 Protein/metabolism; Protein Stability; Ubiquitination

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