HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα

Mu Zhang, Shengyan Xiang, Heui Yun Joo, Lei Wang, Kendra A. Williams, Wei Liu, Chen Hu, Dan Tong, Joshua Haakenson, Chuangui Wang, Shengping Zhang, Ryan E. Pavlovicz, Amanda Jones, Kristina H. Schmidt, Jinfu Tang, Huiqin Dong, Bin Shan, Bin Fang, Rangasudhagar Radhakrishnan, Peter M. GlazerPatrick Matthias, John Koomen, Edward Seto, Gerold Bepler, Santo V. Nicosia, Jiandong Chen, Chenglong Li, Liya Gu, Guo Min Li, Wenlong Bai, Hengbin Wang, Xiaohong Zhang

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)31-46
Number of pages16
JournalMolecular Cell
Volume55
Issue number1
DOIs
StatePublished - Jul 3 2014

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MutS Homolog 2 Protein
Histone Deacetylases
DNA Mismatch Repair
Microsatellite Instability
DNA Adducts
DNA
Proteasome Endopeptidase Complex
Ubiquitin
Cell Cycle Checkpoints
DNA Damage
Down-Regulation
Nucleotides
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Zhang, M., Xiang, S., Joo, H. Y., Wang, L., Williams, K. A., Liu, W., ... Zhang, X. (2014). HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Molecular Cell, 55(1), 31-46. https://doi.org/10.1016/j.molcel.2014.04.028

HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. / 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.

In: Molecular Cell, Vol. 55, No. 1, 03.07.2014, p. 31-46.

Research output: Contribution to journalArticle

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 & Zhang, X 2014, 'HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα', Molecular Cell, vol. 55, no. 1, pp. 31-46. https://doi.org/10.1016/j.molcel.2014.04.028
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. / HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. In: Molecular Cell. 2014 ; Vol. 55, No. 1. pp. 31-46.
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AU - Xiang, Shengyan

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AU - Williams, Kendra A.

AU - Liu, Wei

AU - Hu, Chen

AU - Tong, Dan

AU - Haakenson, Joshua

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AU - Zhang, Shengping

AU - Pavlovicz, Ryan E.

AU - Jones, Amanda

AU - Schmidt, Kristina H.

AU - Tang, Jinfu

AU - Dong, Huiqin

AU - Shan, Bin

AU - Fang, Bin

AU - Radhakrishnan, Rangasudhagar

AU - Glazer, Peter M.

AU - Matthias, Patrick

AU - Koomen, John

AU - Seto, Edward

AU - Bepler, Gerold

AU - Nicosia, Santo V.

AU - Chen, Jiandong

AU - Li, Chenglong

AU - Gu, Liya

AU - Li, Guo Min

AU - Bai, Wenlong

AU - Wang, Hengbin

AU - Zhang, Xiaohong

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