HDAC6 regulates DNA damage response via deacetylating MLH1.
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.
Mesh Terms:
Acetylation, Cell Line, DNA Damage, Histone Deacetylase 6, Humans, MutL Protein Homolog 1, MutL Proteins, MutS DNA Mismatch-Binding Protein, Mutation, Thioguanine
Acetylation, Cell Line, DNA Damage, Histone Deacetylase 6, Humans, MutL Protein Homolog 1, MutL Proteins, MutS DNA Mismatch-Binding Protein, Mutation, Thioguanine
J. Biol. Chem.
Date: Dec. 12, 2018
PubMed ID: 30770470
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