TY - JOUR
T1 - HDAC6 regulates DNA damage response via deacetylating MLH1
AU - Zhang, Mu
AU - Hu, Chen
AU - Moses, Niko
AU - Haakenson, Joshua
AU - Xiang, Shengyan
AU - Quan, Daniel
AU - Fang, Bin
AU - Yang, Zhe
AU - Bai, Wenlong
AU - Bepler, Gerold
AU - Li, Guo Min
AU - Zhang, Xiaohong Mary
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grant R01CA164147 and by Karmanos Cancer Institute startup funds (to X. M. Z.) and Graduate Research Assistantship from Wayne State University (to X. M. Z. and N. M). The authors declare that they have no conflicts of inter-est with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019 Zhang et al.
PY - 2019/4/12
Y1 - 2019/4/12
N2 - 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-thiogua-nine. 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.
AB - 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-thiogua-nine. 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.
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U2 - 10.1074/jbc.RA118.006374
DO - 10.1074/jbc.RA118.006374
M3 - Article
C2 - 30770470
AN - SCOPUS:85064356787
SN - 0021-9258
VL - 294
SP - 5813
EP - 5826
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 15
ER -