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. Glazer; Patrick 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

doi:10.1016/j.molcel.2014.04.028

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 journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	31-46
Number of pages	16
Journal	Molecular cell
Volume	55
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2014.04.028
State	Published - Jul 3 2014

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2014.04.028

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Zhang, M., Xiang, S., Joo, H. Y., Wang, L., Williams, K. A., Liu, W., Hu, C., Tong, D., Haakenson, J., Wang, C., Zhang, S., Pavlovicz, R. E., Jones, A., Schmidt, K. H., Tang, J., Dong, H., Shan, B., Fang, B., Radhakrishnan, R., ... 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

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

@article{a3897bb927004774ad169f050d2d7515,

title = "HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα",

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.",

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

note = "Funding Information: We thank Drs. Saadi Khochbin, Yi Zhang, and Nancy Olashaw for discussion, critical reading, and editing of this manuscript. We thank Drs. Jia Fang, X.-J. Yang, Meera Nanjundan, T.-P. Yao, Stuart L. Schreiber, Ralph Mazitschek, James E. Bradner, and Frank Jirik for reagents, and ICG for funding. We also thank Ms. Wei Guan and Ms. Victoria Izumi at Moffitt Cancer Center for technical assistance. H.W. is a Leukemia and Lymphoma Scholar and is supported by NIH grant GM081489. X.Z. is a K30 Scholar and a Liz Tilberis Scholar. K.A.W. is supported by a USF Graduate Student Success Diversity Fellowship. This work is supported in part by the Marsha Rivkin foundation, the Ovarian Cancer Research Fund (OCRF), the Moffitt Lung Cancer SPORE Career Development Grant, the Bankhead-Coley, James & Esther King Biomedical Program, and NCI grant CA164147 to X.Z. ",

year = "2014",

month = jul,

day = "3",

doi = "10.1016/j.molcel.2014.04.028",

language = "English (US)",

volume = "55",

pages = "31--46",

journal = "Molecular cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα

AU - Zhang, Mu

AU - Xiang, Shengyan

AU - Joo, Heui Yun

AU - Wang, Lei

AU - Williams, Kendra A.

AU - Liu, Wei

AU - Hu, Chen

AU - Tong, Dan

AU - Haakenson, Joshua

AU - Wang, Chuangui

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

N1 - Funding Information: We thank Drs. Saadi Khochbin, Yi Zhang, and Nancy Olashaw for discussion, critical reading, and editing of this manuscript. We thank Drs. Jia Fang, X.-J. Yang, Meera Nanjundan, T.-P. Yao, Stuart L. Schreiber, Ralph Mazitschek, James E. Bradner, and Frank Jirik for reagents, and ICG for funding. We also thank Ms. Wei Guan and Ms. Victoria Izumi at Moffitt Cancer Center for technical assistance. H.W. is a Leukemia and Lymphoma Scholar and is supported by NIH grant GM081489. X.Z. is a K30 Scholar and a Liz Tilberis Scholar. K.A.W. is supported by a USF Graduate Student Success Diversity Fellowship. This work is supported in part by the Marsha Rivkin foundation, the Ovarian Cancer Research Fund (OCRF), the Moffitt Lung Cancer SPORE Career Development Grant, the Bankhead-Coley, James & Esther King Biomedical Program, and NCI grant CA164147 to X.Z.

PY - 2014/7/3

Y1 - 2014/7/3

N2 - 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.

AB - 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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U2 - 10.1016/j.molcel.2014.04.028

DO - 10.1016/j.molcel.2014.04.028

M3 - Article

C2 - 24882211

AN - SCOPUS:84903796100

SN - 1097-2765

VL - 55

SP - 31

EP - 46

JO - Molecular cell

JF - Molecular cell

IS - 1

ER -

HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα

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