Friday, May 9, 2025
5/9/2025
Backup DNA repair in homologous recombination deficient cancers - Abstract The maintenance of genome integrity in homologous recombination deficient (HRD) cancers is linked to the backup repair of DNA double-strand breaks (DSB). Because endogenous DSB in tumors are associated with DNA replication and rapid cell proliferation, there is prompt resection of any DSB to produce a 3’-single-strand tail, which prevents non-homologous end-joining from binding to the ends. The principal backup repair pathways are microhomology mediated end-joining or single stranded annealing in this setting. RAD52 has been identified by our laboratory to be critical for the survival of cells with a defective BRCA1-BRCA2 pathway (HRD). When homologous recombination (HR) becomes inactivated in human cancers, these alternative repair pathways are used, producing the pattern of genome wide changes seen in these cancers. In this setting, RAD52 is a key protein for DSB repair, which works either by the annealing of single-strand tails of broken DNA or by RAD51- mediated strand exchange and gene conversion. The proposed work will determine the role of RAD52, HELQ and POLQ in backup DSB repair. Additional proteins engaged in these functions will be discovered. Their relative contribution to the different types of DSB repair and to the survival of HR-defective cells will be evaluated. The consequences of this work will help to define new approaches to defining targets in the treatment of HRD cancers and allow the development of new functional assays for backup DSB repair, with the ultimate goal of defining the next generation of DNA repair inhibitors beyond PARP-inhibitors. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page
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