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Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors
Journal article   Open access   Peer reviewed

Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors

Fei Huang, Nadish Goyal, Katherine Sullivan, Kritika Hanamshet, Mikir Patel, Olga M Mazina, Charles X Wang, W Frank An, James Spoonamore, Shailesh Metkar, …
Nucleic acids research, v 44(9), pp 4189-4199
19 May 2016
DOI: https://doi.org/10.1093/nar/gkw087
PMID: 26873923
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1093/nar/gkw087View
Published, Version of Record (VoR)CC BY-NC V4.0,  Open

Abstract

Antineoplastic Agents - pharmacology BRCA1 Protein - genetics BRCA1 Protein - metabolism BRCA2 Protein - genetics BRCA2 Protein - metabolism Cell Line, Tumor Cell Survival - drug effects Cisplatin - pharmacology DNA Damage Drug Screening Assays, Antitumor Gene Knockdown Techniques High-Throughput Screening Assays Humans Inhibitory Concentration 50 Protein Binding Rad52 DNA Repair and Recombination Protein - antagonists & inhibitors Rad52 DNA Repair and Recombination Protein - chemistry
RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast cancer and ovarian cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52. The obtained 70 putative inhibitors were further characterized using biochemical and cell-based assays. As a result, we identified compounds that specifically inhibit the biochemical activities of RAD52, suppress growth of BRCA1- and BRCA2-deficient cells and inhibit RAD52-dependent single-strand annealing (SSA) in human cells. We will use these compounds for development of novel cancer therapy and as a probe to study mechanisms of DNA repair.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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