Inhibition of homologous recombination in human cells by targeting RAD51 recombinase

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

doi:10.1021/jm201173g

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Inhibition of homologous recombination in human cells by targeting RAD51 recombinase

Journal article

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Peer reviewed

Inhibition of homologous recombination in human cells by targeting RAD51 recombinase

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

Journal of medicinal chemistry, v 55(7), pp 3011-3020

12 Apr 2012

DOI: https://doi.org/10.1021/jm201173g

PMID: 22380680

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Abstract

Rad51 Recombinase - metabolism

Cell Survival - drug effects

DNA Repair - drug effects

Rad51 Recombinase - genetics

Humans

Rad51 Recombinase - antagonists & inhibitors

Cisplatin - pharmacology

DNA - metabolism

Antineoplastic Agents - chemistry

Mitomycin - pharmacology

DNA - genetics

Drug Synergism

Animals

DNA Breaks, Double-Stranded - drug effects

Nucleoproteins - metabolism

Recombination, Genetic

HEK293 Cells

Cell Line, Tumor

Protein Binding

Antineoplastic Agents - pharmacology

Mice

Quinazolinones - chemistry

Quinazolinones - pharmacology

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.

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Title: Inhibition of homologous recombination in human cells by targeting RAD51 recombinase
Creators: Fei Huang - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA
Olga M Mazina
Isaac J Zentner
Simon Cocklin
Alexander V Mazin
Publication Details: Journal of medicinal chemistry, v 55(7), pp 3011-3020
Publisher: American Chemical Society; Washington, DC
Grant note: CA100839 / NCI NIH HHS 1R21AI087388 / NIAID NIH HHS MH084119 / NIMH NIH HHS R01 CA100839 / NCI NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Biochemistry and Molecular Biology
Web of Science ID: WOS:000302591100011
Scopus ID: 2-s2.0-84859805954
Other Identifier: 991014878192004721

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Web of Science research areas: Chemistry, Medicinal

Inhibition of homologous recombination in human cells by targeting RAD51 recombinase

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Abstract

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UN Sustainable Development Goals (SDGs)

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