Dihydrocoumarin, an HDAC Inhibitor, Increases DNA Damage Sensitivity by Inhibiting Rad52

Int J Mol Sci. 2017 Dec 7;18(12):2655. doi: 10.3390/ijms18122655.

Abstract

Effective DNA repair enables cancer cells to survive DNA damage induced by chemotherapeutic or radiotherapeutic treatments. Therefore, inhibiting DNA repair pathways is a promising therapeutic strategy for increasing the efficacy of such treatments. In this study, we found that dihydrocoumarin (DHC), a flavoring agent, causes deficiencies in double-stand break (DSB) repair and prolonged DNA damage checkpoint recovery in yeast. Following DNA damage, Rad52 recombinase was revealed to be inhibited by DHC, which results in deficiencies in DSB repair and prolonged DNA damage checkpoint recovery. The deletion of RPD3, a class I histone deacetylase (HDAC), was found to mimic DHC-induced suppression of Rad52 expression, suggesting that the HDAC inhibitor activity of DHC is critical to DSB repair and DNA damage sensitivity. Overall, our findings delineate the regulatory mechanisms of DHC in DSB repair and suggest that it might potentially be used as an inhibitor of the DNA repair pathway in human cells.

Keywords: DHC; DNA damage sensitivity; DSB; Rad52; homologous recombination; yeast.

MeSH terms

  • Coumarins / pharmacology
  • Coumarins / toxicity*
  • DNA Damage*
  • Flavoring Agents / pharmacology
  • Flavoring Agents / toxicity*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / toxicity*
  • Rad52 DNA Repair and Recombination Protein / antagonists & inhibitors*
  • Recombinational DNA Repair
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*

Substances

  • Coumarins
  • Flavoring Agents
  • Histone Deacetylase Inhibitors
  • RAD52 protein, S cerevisiae
  • Rad52 DNA Repair and Recombination Protein
  • Saccharomyces cerevisiae Proteins
  • 3,4-dihydrocoumarin