Abstract
The breast cancer susceptibility gene 1/2 (BRCA1/2) is frequently mutated in many malignant tumors, such as breast cancer and ovarian cancer. Studies have demonstrated that inhibition of RAD52 gene function in BRCA2-deficient cancer causes synthetic lethality, suggesting a potential application of RAD52 in cancer-targeted therapy. In this study, we have performed a virtual screening by targeting the self-association domain (residues 85–159) of RAD52 with a library of 66,608 compounds and found one compound, C791-0064, that specifically inhibited the proliferation of BRCA2-deficient cancer cells. Our biochemical and cell-based experimental data suggested that C791-0064 specifically bound to RAD52 and disrupted the single-strand annealing activity of RAD52. Taken together, C791-0064 is a promising leading compound worthy of further exploitation in the context of BRCA-deficient targeted cancer therapy.
Highlights
Breast cancer is one of the most commonly diagnosed types of cancer in women throughout the world, contributing to about 30% of newly diagnosed cases and 14% of cancer-related deaths in women (Siegel et al, 2018)
Even though the function of higher eukaryotes RAD52 in homologous recombination and other DNA repair pathways is getting clearer with progresses in genetics and biochemical studies (Benson et al, 1998; Mcilwraith and West, 2008; Jalan et al, 2019), its exact role in BRCAdeficient mammalian cells has not been fully dissected
Several studies have demonstrated that RAD52 is required for the survival of cells with loss-of-function mutation in genes such as breast cancer susceptibility gene 1/2 (BRCA1/2), PALB2, and RAD51 paralogs, which is not the case for normal cells
Summary
Breast cancer is one of the most commonly diagnosed types of cancer in women throughout the world, contributing to about 30% of newly diagnosed cases and 14% of cancer-related deaths in women (Siegel et al, 2018). The success of PARP inhibitors in treating BRCA1/2-mutated tumors has demonstrated the efficacy of cancer-targeted therapy exploiting synthetic lethality (Lord et al, 2015). The synthetic lethality between RAD52 and BRCA1/2 has long been established (Feng et al, 2011; Lok et al, 2013), identifying RAD52 as a potential therapeutic target against cancers with BRCA1/2 gene mutations. A series of studies have demonstrated that the RAD52 ring structure is critical to its activity in promoting annealing complementary DNA strands during different repair pathways (Grimme et al, 2010; Hanamshet et al, 2016). Disruption of the RAD52 ring structure, that is, abolishing RAD52 function in DNA repair, will lead to specific killing of the cell with BRCA deficiency
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