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HDAC6 regulates DNA damage response via deacetylating MLH1.

ABSTRACT: MutL homolog 1 (MLH1) is a key DNA mismatch repair protein, which plays an important role in maintenance of genomic stability and the DNA damage response. Here, we report that MLH1 is a novel substrate of histone deacetylase 6 (HDAC6). HDAC6 interacts with and deacetylates MLH1 both in vitro and in vivo Interestingly, deacetylation of MLH1 blocks the assembly of the MutS?-MutL? complex. Moreover, we have identified four novel acetylation sites in MLH1 by MS analysis. The deacetylation mimetic mutant, but not the WT and the acetylation mimetic mutant, of MLH1 confers resistance to 6-thioguanine. Overall, our findings suggest that the MutS?-MutL? complex serves as a sensor for DNA damage response and that HDAC6 disrupts the MutS?-MutL? complex by deacetylation of MLH1, leading to the tolerance of DNA damage.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6463726 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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HDAC6 regulates DNA damage response via deacetylating MLH1.

Zhang Mu M Hu Chen C Moses Niko N Haakenson Joshua J Xiang Shengyan S Quan Daniel D Fang Bin B Yang Zhe Z Bai Wenlong W Bepler Gerold G Li Guo-Min GM Zhang Xiaohong Mary XM

The Journal of biological chemistry 20190215 15

MutL homolog 1 (MLH1) is a key DNA mismatch repair protein, which plays an important role in maintenance of genomic stability and the DNA damage response. Here, we report that MLH1 is a novel substrate of histone deacetylase 6 (HDAC6). HDAC6 interacts with and deacetylates MLH1 both <i>in vitro</i> and <i>in vivo</i> Interestingly, deacetylation of MLH1 blocks the assembly of the MutSα-MutLα complex. Moreover, we have identified four novel acetylation sites in MLH1 by MS analysis. The deacetylat ...[more]

PMID: 30770470

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