期刊
ELIFE
卷 5, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.14740
关键词
DNA repair; RAD52; high throughput screening; small-molecule inhibitors; homologous recombination; replication; stalled replication forks; BRCA2; MUS81; breast cancer; synthetic lethality; DNA double strand breaks
类别
资金
- American Cancer Society Research Scholar Grant [RSG-09-182-01-DMC]
- NIH [R01-GM097373, S10 1S10RR029274-01]
- University of Iowa College of Medicine pilot HTS
- Italian Association of Cancer Research (AIRC) [IG13398]
- Nando-Peretti Foundation [2012-113]
- UIHTS facility
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) Brazil
The DNA repair protein RAD52 is an emerging therapeutic target of high importance for BRCA-deficient tumors. Depletion of RAD52 is synthetically lethal with defects in tumor suppressors BRCA1, BRCA2 and PALB2. RAD52 also participates in recovery of the stalled replication forks. Anticipating that ssDNA binding activity underlies the RAD52 cellular functions, we carried out a high throughput screening campaign to identify compounds that disrupt the RAD52-ssDNA interaction. Lead compounds were confirmed as RAD52 inhibitors in biochemical assays. Computational analysis predicted that these inhibitors bind within the ssDNA-binding groove of the RAD52 oligomeric ring. The nature of the inhibtor-RAD52 complex was validated through an in silico screening campaign, culminating in the discovery of an additional RAD52 inhibitor. Cellular studies with our inhibitors showed that the RAD52-ssDNA interaction enables its function at stalled replication forks, and that the inhibition of RAD52-ssDNA binding acts additively with BRCA2 or MUS81 depletion in cell killing.
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