Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

SIMPLE SUMMARY: RAD51 is an essential gene for cell survival. Its function is central to DNA repair and it protects cells from life-threatening damage to the genome. Interestingly, RAD51 is expressed at high levels in a large proportion of cancers, and elevated RAD51 expression is associated with a bad outcome and reduced response to treatment. Hence, reducing RAD51 expression and/or interfering with its function could be of great therapeutic value. We review here the multiple levels of regulation of RAD51 expression and function and explore potential therapeutic leads. ABSTRACT: The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed.