HDAC6 Deacetylates and Ubiquitinates MSH2 to Maintain Proper Levels of MutSα

MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutS alpha) and MSH2-MSH3 (MutS beta) heterodimers, which help to ensure genomic integrity. MutS alpha 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 MutS alpha from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutS alpha 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 MutS alpha are maintained.