A novel DNA repair inhibitor, diallyl disulfide (DADS), impairs DNA resection during DNA double-strand break repair by reducing Sae2 and Exo1 levels

DNA Repair (Amst). 2019 Oct;82:102690. doi: 10.1016/j.dnarep.2019.102690. Epub 2019 Aug 24.

Abstract

Combining natural products with chemotherapy and/or radiotherapy may increase the efficacy of cancer treatment. It has been hypothesized that natural products may inhibit DNA repair and sensitize cancer cells to DNA damage-based cancer therapy. However, the molecular mechanisms underlying these activities remain unclear. In this study, we found that diallyl disulfide (DADS), an organosulfur compound, increased the sensitivity of yeast cells to DNA damage and has potential for development as an adjuvant drug for DNA damage-based cancer therapy. We induced HO endonuclease to generate a specific DNA double-strand break (DSB) by adding galactose to yeast and used this system to study how DADS affects DNA repair. In this study, we found that DADS inhibited DNA repair in single-strand annealing (SSA) system and sensitized SSA cells to a single DSB. DADS impaired DNA repair by inhibiting the protein levels of the DNA resection-related proteins Sae2 and Exo1. We also found that the recruitment of MRX and the Mec1-Ddc2 complex to a DSB was prevented by DADS. This result suggests that DADS counteracts G2/M DNA damage checkpoint activation in a Mec1 (ATR)- and Tel1 (ATM)-dependent manner. Only by elucidating the molecular mechanisms by which DADS influences DNA repair will we be able to discover new adjuvant drugs to improve chemotherapy and/or radiotherapy.

Keywords: DNA damage checkpoint; DNA repair; DNA resection; Diallyl disulfide; Homologous recombination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allyl Compounds / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Autophagic Cell Death / drug effects
  • Autophagic Cell Death / genetics
  • DNA Breaks, Double-Stranded / drug effects*
  • DNA Repair / drug effects*
  • Disulfides / pharmacology*
  • Drug Synergism
  • Endonucleases / metabolism*
  • Exodeoxyribonucleases / metabolism*
  • Proteolysis / drug effects
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Allyl Compounds
  • Disulfides
  • SAE2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • diallyl disulfide
  • Endonucleases
  • Exodeoxyribonucleases
  • exodeoxyribonuclease I