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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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:HDAC6

GO:0031648: protein destabilization

ECO:0000315:

P

The organism is H. Sapiens and the protein is HDAC6 or (Histone deacetylase 6) Figure 3C shows that knockdown of HDAC6 lowers the half life of MSH2 (MutS protein homolog 2) and “As shown in Figure 3C, wild-type HDAC6 (F-HD6, lanes 17–20), not the catalytically dead mutant of HDAC6 (F-HD6DM, lanes 13–16) or the DAC1-deficient mutant of HDAC6 (F-HD6[439–1215], lanes 21–24), could reduce the half-life of MSH2. “ Thus HDAC6 destabilizes MSH2

complete
CACAO 13035

MOUSE:HDAC6

GO:0000209: protein polyubiquitination

ECO:0000315:

P

The Organism is Mus Musculus and the protein is HDAC6. Figure 4B shows that knocking out HDAC6 stops polyubiquitination and reintroducing wild type HDAC6 restores polyubiquitination of protein MSH2

complete
CACAO 13048

MOUSE:HDAC6

GO:0016575: histone deacetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Mouse; HDAC6

According to Figure 5C, HDAC6 is involved in core histone deacetylation.

complete
CACAO 13049

MOUSE:HDAC6

GO:0004407: histone deacetylase activity

ECO:0000315:

F

Mouse; HDAC6

According to Figure 5C, HDAC6 is involved in core histone deacetylation.

complete
CACAO 13050

Notes

See also

References

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