Inhibition of Homologous Recombination in Human Cells by Targeting RAD51 Recombinase

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 screeni...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3011-3020
Main Authors: Huang, Fei, Mazina, Olga M, Zentner, Isaac J, Cocklin, Simon, Mazin, Alexander V
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm201173g