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Issue 34, 2018
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Compound F779-0434 causes synthetic lethality in BRCA2-deficient cancer cells by disrupting RAD52–ssDNA association

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Abstract

Maintenance of genomic integrity is essential for the survival of all organisms. Homologous recombination (HR) is the major pathway for high-fidelity repair of DNA double-stranded breaks (DSBs). In addition to the classic BRCA–RAD51 pathway, another secondary HR sub-pathway dependent on RAD52 has been suggested to be functioning in mammalian cells. Importantly, RAD52 has been shown to be synthetically lethal to BRCA1/2-deficient cells, rendering RAD52 to be a desirable target in cancer therapy. In the current study, we performed a structure-based virtual screening of 47 737 drug-like compounds to identify RAD52-specific inhibitors. The top ranked virtual screening hits were further characterized using molecular dynamics simulation and biochemical and cell-based assays. We found that one compound, namely, F779-0434 specifically suppressed the growth of BRCA2-deficient cells and disrupted RAD52–ssDNA interaction in vitro. This RAD52-specific inhibitor identified in the current study is a promising compound for targeted cancer therapy, and it can also be used as a probe to study the mechanisms of DNA repair in human cells.

Graphical abstract: Compound F779-0434 causes synthetic lethality in BRCA2-deficient cancer cells by disrupting RAD52–ssDNA association

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Supplementary files

Article information


Submitted
05 Mar 2018
Accepted
04 May 2018
First published
23 May 2018

This article is Open Access

RSC Adv., 2018,8, 18859-18869
Article type
Paper

Compound F779-0434 causes synthetic lethality in BRCA2-deficient cancer cells by disrupting RAD52–ssDNA association

J. Li, Q. Yang, Y. Zhang, K. Huang, R. Sun and Q. Zhao, RSC Adv., 2018, 8, 18859
DOI: 10.1039/C8RA01919C

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