Abstract 1465: RAD52 and ERCC6L/PICH have a compensatory relationship for genome stability

Abstract Human RAD52 plays essential roles in several homology-driven DNA repair pathways, including single strand annealing, transcription-coupled homologous recombination, and mitotic DNA synthesis (MiDAS). Although RAD52 is not essential, RAD52 loss with disruption of either the breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) genes is synthetic lethal. Thus, RAD52 is an intriguing potential target for treatment of BRCA-deficient cancers. However, the full breadth of pathways and factors that create a state of RAD52-dependence when compromised are not understood. To query RAD52 synthetic lethal relationships, we performed genome-wide CRISPR knock-out screens and identified hundreds of candidate synthetic lethal interactions. We then performed secondary screening and identified genes for which depletion causes reduced viability and elevated genome instability (increased 53BP1 nuclear foci) in RAD52-deficient cells. One such factor was ERCC6L, which marks DNA bridges during anaphase, and hence is important for genome stability in mitosis. Additionally, pan-cancer studies of altered ERCC6L expression have identified increased ERCC6L expression as a marker of poor prognosis in multiple types of cancer, making it a relevant target for cancer therapy. Thus, we investigated the functional interrelationship between RAD52 and ERCC6L. We found that RAD52 deficiency increases ERCC6L-coated anaphase ultrafine bridges, and that ERCC6L depletion causes elevated RAD52 foci in prometaphase and interphase cells. These effects were enhanced with replication stress (i.e. hydroxyurea) and topoisomerase IIα inhibition (ICRF-193), where post-treatment effect timings were consistent with defects in addressing stress in mitosis. Altogether, we suggest that RAD52 and ERCC6L co-compensate to protect genome stability in mitosis. Citation Format: Beth Osia, Arianna Merkell, Felicia Wednesday Lopezcolorado, Xiaoli Ping, Jeremy M. Stark. RAD52 and ERCC6L/PICH have a compensatory relationship for genome stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1465.