title: Curcumin-Mediated HDAC Inhibition Suppresses the DNA Damage Response and Contributes to Increased DNA Damage Sensitivity.
abstract: Chemo- and radiotherapy cause multiple forms of DNA damage and lead to the death of cancer cells. Inhibitors of the DNA damage response are candidate drugs for use in combination therapies to increase the efficacy of such treatments. In this study, we show that curcumin, a plant polyphenol, sensitizes budding yeast to DNA damage by counteracting the DNA damage response. Following DNA damage, the Mec1-dependent DNA damage checkpoint is inactivated and Rad52 recombinase is degraded by curcumin, which results in deficiencies in double-stand break repair. Additive effects on damage-induced apoptosis and the inhibition of damage-induced autophagy by curcumin were observed. Moreover, rpd3 mutants were found to mimic the curcumin-induced suppression of the DNA damage response. In contrast, hat1 mutants were resistant to DNA damage, and Rad52 degradation was impaired following curcumin treatment. These results indicate that the histone deacetylase inhibitor activity of curcumin is critical to DSB repair and DNA damage sensitivity.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Pei-Ya
authors.initials: PY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ya-Chen
authors.initials: YC
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ju-Sui
authors.initials: JS
authors.lastname: Huang
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yi-Tsen
authors.initials: YT
authors.lastname: Kuo
authors.affiliation: Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Jen-Chine
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003474:Curcumin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004351:Drug Resistance / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry*; D015151:Immunoblotting; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D003474:Curcumin