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Nucleic Acids Res DOI:10.1093/nar/gkw087

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

Publication TypeJournal Article
Year of Publication2016
AuthorsHuang, F, Goyal, N, Sullivan, K, Hanamshet, K, Patel, M, Mazina, OM, Wang, CX, W An, F, Spoonamore, J, Metkar, S, Emmitte, KA, Cocklin, S, Skorski, T, Mazin, AV
JournalNucleic Acids Res
Date Published2016 May 19

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.


Alternate JournalNucleic Acids Res.
PubMed ID26873923
PubMed Central IDPMC4872086
Grant ListR01 CA186238 / CA / NCI NIH HHS / United States