Abstract 1187 A novel activity of the RAD52 protein that is essential for the viability of BRCA-deficient breast and ovarian cancer cells

• DOI: 10.1016/j.jbc.2024.106524
• Publication Date: 2024-03-25T22:01:55Z
• Authors: Alexander Mazin; Matthew Rossi; Olga Mazina; Shuming Liu; Simranjeet Sekhon; Sarah DiDomenico
• Keywords: RAD52

RAD52 functions in homologous recombination (HR): a major pathway for repair of DNA double-strand breaks (DSBs), the most lethal lesion type. HR is also essential faithful segregation chromosomes during gametogenesis. Disfunctions lead to genome instability causing cancer or infertility. Mutations genes BRCA1 and BRCA2 are responsible nearly half all hereditary breast ovarian cancers. While mutations cause no discernible phenotype normal human cells; BRCA1/2-deficient cells, inactivation becomes lethal. This synthetically BRCA/RAD52 relationship renders promising therapeutic target. However, mechanism underlying RAD52-BRCA synthetic lethality poorly understood. The recombinase RAD51 plays central role HR. binds ssDNA promotes search undamaged dsDNA generate joint molecules (D-loops) that provide template DSB repair. BRCA-deficient cells activity suppressed. We found previously protein catalyzes pairing. it does so an inverse way, by forming complex with promoting strand exchange ssDNA. RAD52-dsDNA can interact RNA resulting formation DNA-RNA hybrids. Here, using biochemical, biophysical, structural methods we investigated this novel activity. generation highly stable recombinational intermediates: double-D-loops RNA-D-loops (R/D-loops). suggest non-canonical pairing contributes viability cells. These findings will facilitate our ongoing work developing inhibitors targeting Funding: R01 GM136717, CA23728 (A.V.M.). Congressionally Directed Medical Research Programs BC191160 (AV.M.) A.V.M. holder Joe R. Teresa Lozano Long Chair Cancer recipient CPRIT REI Award (RR210023) UT System Faculty STARs Award.