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 language | English (US) |
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Pages (from-to) | 3011-3020 |
Number of pages | 10 |
Journal | Journal of Medicinal Chemistry |
Volume | 55 |
Issue number | 7 |
DOIs | |
State | Published - Apr 12 2012 |
Externally published | Yes |
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine