HDAC6 regulates DNA damage response via deacetylating MLH1

Mu Zhang, Chen Hu, Niko Moses, Joshua Haakenson, Shengyan Xiang, Daniel Quan, Bin Fang, Zhe Yang, Wenlong Bai, Gerold Bepler, Guo-Min Li, Xiaohong Mary Zhang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5813-5826
Number of pages14
JournalJournal of Biological Chemistry
Volume294
Issue number15
DOIs
StatePublished - Jan 1 2019

Fingerprint

Histone Deacetylases
DNA Damage
Acetylation
DNA
Repair
DNA Mismatch Repair
Genomic Instability
MutL Protein Homolog 1
Sensors
Substrates
Maintenance
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Zhang, M., Hu, C., Moses, N., Haakenson, J., Xiang, S., Quan, D., ... Zhang, X. M. (2019). HDAC6 regulates DNA damage response via deacetylating MLH1. Journal of Biological Chemistry, 294(15), 5813-5826. https://doi.org/10.1074/jbc.RA118.006374

HDAC6 regulates DNA damage response via deacetylating MLH1. / Zhang, Mu; Hu, Chen; Moses, Niko; Haakenson, Joshua; Xiang, Shengyan; Quan, Daniel; Fang, Bin; Yang, Zhe; Bai, Wenlong; Bepler, Gerold; Li, Guo-Min; Zhang, Xiaohong Mary.

In: Journal of Biological Chemistry, Vol. 294, No. 15, 01.01.2019, p. 5813-5826.

Research output: Contribution to journalArticle

Zhang, M, Hu, C, Moses, N, Haakenson, J, Xiang, S, Quan, D, Fang, B, Yang, Z, Bai, W, Bepler, G, Li, G-M & Zhang, XM 2019, 'HDAC6 regulates DNA damage response via deacetylating MLH1', Journal of Biological Chemistry, vol. 294, no. 15, pp. 5813-5826. https://doi.org/10.1074/jbc.RA118.006374
Zhang M, Hu C, Moses N, Haakenson J, Xiang S, Quan D et al. HDAC6 regulates DNA damage response via deacetylating MLH1. Journal of Biological Chemistry. 2019 Jan 1;294(15):5813-5826. https://doi.org/10.1074/jbc.RA118.006374
Zhang, Mu ; Hu, Chen ; Moses, Niko ; Haakenson, Joshua ; Xiang, Shengyan ; Quan, Daniel ; Fang, Bin ; Yang, Zhe ; Bai, Wenlong ; Bepler, Gerold ; Li, Guo-Min ; Zhang, Xiaohong Mary. / HDAC6 regulates DNA damage response via deacetylating MLH1. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 15. pp. 5813-5826.
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