Abstract
RAD52 is a structurally and functionally conserved component of the DNA double-strand break (DSB) repair apparatus from budding yeast to humans. We recently showed that expressing the human gene, HsRAD52 in rad52 mutant budding yeast cells can suppress both their ionizing radiation (IR) sensitivity and homologous recombination repair (HRR) defects. Intriguingly, we observed that HsRAD52 supports DSB repair by a mechanism of HRR that conserves genome structure and is independent of the canonical HR machinery. In this study we report that naturally occurring variants of HsRAD52, one of which suppresses the pathogenicity of BRCA2 mutations, were unable to suppress the IR sensitivity and HRR defects of rad52 mutant yeast cells, but fully suppressed a defect in DSB repair by single-strand annealing (SSA). This failure to suppress both IR sensitivity and the HRR defect correlated with an inability of HsRAD52 protein to associate with and drive an interaction between genomic sequences during DSB repair by HRR. These results suggest that HsRAD52 supports multiple, distinct DSB repair apparatuses in budding yeast cells and help further define its mechanism of action in HRR. They also imply that disruption of HsRAD52-dependent HRR in BRCA2-defective human cells may contribute to protection against tumorigenesis and provide a target for killing BRCA2-defective cancers.
Highlights
Ionizing radiation (IR) is a ubiquitous component of our environment that arises from both natural and manmade sources
Expression of the human RAD52 (HsRAD52)-G59R and HsRAD52-S346X variant alleles in budding yeast cells produce stable proteins As HsRAD52 plays a role in double-strand break (DSB) repair by homologous recombination repair (HRR) [19,20,21] and defects in HRR are linked to cancer susceptibility [31,32,33,34], we reasoned that variants of HsRAD52 from patients with cancer might confer loss of protein function
In support of this diversification, we previously demonstrated that HsRAD52 possesses the distinct ability to promote repair of DSBs by conservative HRR in budding yeast independently from the canonical HRR apparatus [29], which may be similar to its function in mammalian cells [20, 22, 65]
Summary
Ionizing radiation (IR) is a ubiquitous component of our environment that arises from both natural and manmade sources. The most prominent of these mechanisms are homologous recombination repair (HRR) and non-homologous end joining (NHEJ), which are genetically and biochemically distinct These distinctions are the basis of the different outcomes of DSB repair by HRR and NHEJ, with HRR most frequently conserving genome structure and NHEJ frequently altering it [12,13,14]. The balance between these conservative and non-conservative mechanisms of DSB repair can have profound effects on genome integrity and human health following exposure to IR [15]
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