Molecular pathways: understanding the role of Rad52 in homologous recombination for therapeutic advancement.
The Rad52 protein was largely ignored in humans and other mammals when the mouse knockout revealed a largely "no-effect" phenotype. However, using synthetic lethal approaches to investigate context-dependent function, new studies have shown that Rad52 plays a key survival role in cells lacking the function of the breast cancer type 1 susceptibility protein (BRCA1)-BRCA2 pathway of homologous recombination. Biochemical studies also showed significant differences between yeast and human Rad52 (hRad52), in which yeast Rad52 can promote strand invasion of replication protein A (RPA)-coated single-stranded DNA (ssDNA) in the presence of Rad51 but hRad52 cannot. This results in the paradox of how is hRad52 providing Rad51 function: presumably there is something missing in the biochemical assays that exists in vivo, but the nature of this missing factor is currently unknown. Recent studies have suggested that Rad52 provides back-up Rad51 function for all members of the BRCA1-BRCA2 pathway, suggesting that Rad52 may be a target for therapy in BRCA pathway-deficient cancers. Screening for ways to inhibit Rad52 would potentially provide a complementary strategy for targeting BRCA-deficient cancers in addition to poly (ADP-ribose) polymerase (PARP) inhibitors.
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Benjamin H
BH
Lok
Simon N
SN
Powell
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000076164:Fanconi Anemia Complementation Group N Protein; D059765:Homologous Recombination; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; D025521:Tumor Suppressor Proteins; D051135:Rad51 Recombinase