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

Radhakrishnan, R.; Li, Yixuan; Xiang, Shengyan; Yuan, Fenghua; Yuan, Zhigang; Telles, Elphine; Fang, Jia; Coppola, Domenico; Shibata, David; Lane, William S.; Zhang, Yanbin; Zhang, Xiaohong; Seto, Edward

doi:10.1074/jbc.m114.612945

Cited by 49 publications

(47 citation statements)

References 28 publications

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“…HDAC6 sequentially deacetylates and ubiquitinates MSH2, causing a cellular tolerance to DNA damage and decreased cellular DNA mismatch repair activities by downregulation of MSH2 (Zhang et al 2014). However, the deacetylation of MSH2 by HDAC10 might promote DNA mismatch repair activity (Radhakrishnan et al 2015). …”

Section: Possible Mechanisms Of Hdacs In Cancer Developmentmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

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874

765

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Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Post-translational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling and nuclear architecture. Histone acetylation, a well-studied post-translational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous non-histone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.

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Section: Possible Mechanisms Of Hdacs In Cancer Developmentmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

Self Cite

874

765

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“…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. 52 Also, enzymes involved in Okazaki fragment maturation are influenced by acetylation to promote strand displacement synthesis.…”

Section: Mismatch (mentioning

confidence: 99%

“…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. We focused on analyzing two DNA repair mechanisms, MMR and BER.…”

Section: Introductionmentioning

confidence: 99%

Acetylation regulates DNA repair mechanisms in human cells

2016

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The p300-mediated acetylation of enzymes involved in DNA repair and replication has been previously shown to stimulate or inhibit their activities in reconstituted systems. To explore the role of acetylation on DNA repair in cells we constructed plasmid substrates carrying inactivating damages in the EGFP reporter gene, which should be repaired in cells through DNA mismatch repair (MMR) or base excision repair (BER) mechanisms. We analyzed efficiency of repair within these plasmid substrates in cells exposed to deacetylase and acetyltransferase inhibitors, and also in cells deficient in p300 acetyltransferase. Our results indicate that protein acetylation improves DNA mismatch repair in MMR-proficient HeLa cells and also in MMR-deficient HCT116 cells. Moreover, results suggest that stimulated repair of mismatches in MMR-deficient HCT116 cells is done though a strand-displacement synthesis mechanism described previously for Okazaki fragments maturation and also for the EXOI-independent pathway of MMR. Loss of p300 reduced repair of mismatches in MMR-deficient cells, but did not have evident effects on BER mechanisms, including the long patch BER pathway. Hypoacetylation of the cells in the presence of acetyltransferase inhibitor, garcinol generally reduced efficiency of BER of 8-oxoG damage, indicating that some steps in the pathway are stimulated by acetylation.

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“…Acetylation of MSH2, by a hereto unknown mechanism, increases its stability and therefore contributes to mismatch detection and effective MMR. HDAC6 and 10 have been shown to deacetylate MSH2 (89,90). HDAC6 is predominantly found in the cytoplasm of cells (91,92), but upon the induction of DNA damage (89) or differentiation (93), a fraction of HDAC6 becomes nuclear.…”

Section: Introductionmentioning

confidence: 99%

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

Roos¹,

Krumm²

2016

Nucleic Acids Res

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Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD+ dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair. Furthermore, we discuss possible mechanisms whereby these histone/protein deacetylases facilitate the switch between DNA double-strand break (DSB) repair pathways, how SIRTs play a central role in the crosstalk between DNA repair and cell death pathways due to their dependence on NAD+, and the influence of small molecule HDAC inhibitors (HDACi) on cancer cell resistance to genotoxin based therapies. Throughout the review, we endeavor to identify the specific HDAC targeted by HDACi leading to therapy sensitization.

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

Cited by 49 publications

References 28 publications

HDACs and HDAC Inhibitors in Cancer Development and Therapy

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Acetylation regulates DNA repair mechanisms in human cells

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

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