title: Inhibition of homologous recombination in human cells by targeting RAD51 recombinase.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Olga M
authors.initials: OM
authors.lastname: Mazina
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Zentner
authors.forename: Simon
authors.initials: S
authors.lastname: Cocklin
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mazin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D009698:Nucleoproteins / Q000378:metabolism; D011485:Protein Binding; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic
chemical_list: D000970:Antineoplastic Agents; D009698:Nucleoproteins; D052999:Quinazolinones; D016685:Mitomycin; D004247:DNA; D051135:Rad51 Recombinase; D002945:Cisplatin