HDAC6 regulates DNA damage response via deacetylating MLH1.

MLH1 is a key DNA mismatch repair (MMR) protein, which plays an important role in maintenance of genomic stability and the DNA damage response (DDR). Here, we report that MLH1 is a novel substrate of HDAC6. HDAC6 interacts with and deacetylates MLH1 both in vitro and in vivo. Interestingly, deacetylation of MLH1 blocks the assembly of the MutSα-MutLa complex. Moreover, we have identified four novel acetylation sites in MLH1 by mass spectrometry analysis. The deacetylation mimetic mutant, but not the wild-type and the acetylation mimetic mutant, of MLH1 confers resistance to 6-thioguanine. Overall, our findings suggest that the MutSa-MutLa complex serves as a sensor for DNA damage response and that HDAC6 disrupts the MutSa-MutLa complex by deacetylation of MLH1, leading to the tolerance of DNA damage.