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Huang F , Goyal N , Sullivan K , Hanamshet K , Patel M , Mazina OM , Wang CX , An WF , Spoonamore J , Metkar S , Emmitte KA , Cocklin S , Skorski T , Mazin AV
Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors
Nucleic Acids Res. 2016 May 19;44(9) :4189-99
PMID: 26873923 PMCID: PMC4872086
AbstractRAD52 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.
Notes1362-4962 Huang, Fei Goyal, Nadish Sullivan, Katherine Hanamshet, Kritika Patel, Mikir Mazina, Olga M Wang, Charles X An, W Frank Spoonamore, James Metkar, Shailesh Emmitte, Kyle A Cocklin, Simon Skorski, Tomasz Mazin, Alexander V P30 CA006927/CA/NCI NIH HHS/United States R01 CA186238/CA/NCI NIH HHS/United States R01 CA188347/CA/NCI NIH HHS/United States Journal Article England Nucleic Acids Res. 2016 May 19;44(9):4189-99. doi: 10.1093/nar/gkw087. Epub 2016 Feb 11.