| First Author | Zhang M | Year | 2014 |
| Journal | Mol Cell | Volume | 55 |
| Issue | 1 | Pages | 31-46 |
| PubMed ID | 24882211 | Mgi Jnum | J:215334 |
| Mgi Id | MGI:5605128 | Doi | 10.1016/j.molcel.2014.04.028 |
| Citation | Zhang M, et al. (2014) HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSalpha. Mol Cell 55(1):31-46 |
| abstractText | MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutSalpha) and MSH2-MSH3 (MutSbeta) heterodimers, which help to ensure genomic integrity. MutSalpha 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 MutSalpha from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutSalpha 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 MutSalpha are maintained. |
