Inhibition of Homologous Recombination in Human Cells by Targeting RAD51 Recombinase

J Med Chem. 2012 Apr 12;55(7):3011-20. doi: 10.1021/jm201173g. Epub 2012 Mar 19.

Abstract

The homologous recombination (HR) pathway plays a crucial role in the repair of DNA double-strand breaks (DSBs) and interstrand cross-links (ICLs). RAD51, a key protein of HR, possesses a unique activity: DNA strand exchange between homologous DNA sequences. Recently, using a high-throughput screening (HTS), we identified compound 1 (B02), which specifically inhibits the DNA strand exchange activity of human RAD51. Here, we analyzed the mechanism of inhibition and found that 1 disrupts RAD51 binding to DNA. We then examined the effect of 1 on HR and DNA repair in the cell. The results show that 1 inhibits HR and increases cell sensitivity to DNA damage. We propose to use 1 for analysis of cellular functions of RAD51. Because DSB- and ICL-inducing agents are commonly used in anticancer therapy, specific inhibitors of RAD51 may also help to increase killing of cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • DNA / genetics
  • DNA / metabolism
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Repair / drug effects
  • Drug Synergism
  • HEK293 Cells
  • Humans
  • Mice
  • Mitomycin / pharmacology
  • Nucleoproteins / metabolism
  • Protein Binding
  • Quinazolinones / chemistry*
  • Quinazolinones / pharmacology
  • Rad51 Recombinase / antagonists & inhibitors*
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Recombination, Genetic

Substances

  • Antineoplastic Agents
  • Nucleoproteins
  • Quinazolinones
  • Mitomycin
  • DNA
  • Rad51 Recombinase
  • Cisplatin