Compound F779-0434 causes synthetic lethality in BRCA2-deficient cancer cells by disrupting RAD52–ssDNA association. Issue 34 (23rd May 2018)

• Record Type: Journal Article
• Authors: Li, Jian; Yang, Qianye; Zhang, Yang; Huang, Kejia; Sun, Rong; Zhao, Qi
• Is Part Of: RSC advances. Volume 8:Issue 34(2018)
• Page Start: 18859
• Page End: 18869
• Publication Date: 2018-05-23
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8ra01919c
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : A novel compound named F779-0434 caused synthetic lethality in BRCA2-deficient cancer cells by disrupting RAD52–ssDNA associations. 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.