Inhibition of homologous recombination in human cells by targeting RAD51 recombinase

Fei Huang, Olga M. Mazina, Isaac J. Zentner, Simon Cocklin, Alexander V. Mazin

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3011-3020
Number of pages10
JournalJournal of Medicinal Chemistry
Volume55
Issue number7
DOIs
StatePublished - Apr 12 2012
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

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