HDAC6 Deacetylates and Ubiquitinates MSH2 to Maintain Proper Levels of MutSα

Abstract

SUMMARY 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.

Histone Deacetylase 10 Regulates DNA Mismatch Repair and May Involve the Deacetylation of MutS Homolog 2

“…Previous studies show that Hda1, a yeast Class II HDAC, interacts with MSH2 (22). Consistent with these studies, a recent study shows that a Class IIb HDAC, HDAC6, interacts with MSH2 (18). However, it remains unclear whether other HDACs also bind MSH2.…”

“…MSH2 Is Acetylated at Lysine 73-Four acetylation sites, Lys-845, Lys-847, Lys-871, and Lys-892, have been identified at the MSH2 C terminus by mass spectrometry (18). However, mutation of these four sites from lysine to arginine still allows for a modest level of acetylation when compared with that of wild type (18), suggesting that additional acetylation sites exist in MSH2.…”

“…Two studies showed that depletion or inhibition of HDAC6 sensitizes cancer cells to compounds such as cisplatin, etoposide, and doxorubicin (16,17). Recent evidence shows that HDAC6 deacetylates and ubiquitinates MSH2, and modulates the DNA damage response and MMR activity (18). However, whether MSH2 is regulated by other HDACs (in addition to HDAC6) and HATs is largely unknown.…”

Acetylation regulates DNA repair mechanisms in human cells

“…Acetylation of K residues at the C termini of MSH2 promoted formation of stable MutSa complexes. 19 Interestingly, other studies suggest that deacetylation of K residue on N termini of MSH2 promotes DNA MMR activity. 20 Acetylation was also detected in components of endonuclease MutLa, MLH1 and PMS2, as well as in EXO1.…”

“…Here, acetylation of K residues at the C termini of MSH2, an especial component of the complex recognizing mismatches in DNA, had a positive effect on repair. 19 Interestingly, deacetylation of N termini in MSH2 also had a positive effect on MMR in reconstituted systems. 20 In this study, our goal was to determine the effect of acetylation on DNA repair mechanisms in cell-based systems using plasmid constructs bearing damage sites in the EGFP gene and monitoring its repair.…”