Abstract 2371: FBXL12 modulates Fanconi anaemia-BRCA signaling under conditions of oncogene-induced replication stress

Oncogene-induced replication stress (OIRS) constitutes an early obstacle to cancer progression. De-regulation of cell death or senescence programs contribute to overcoming this barrier. However, even after escaping these fail-safe mechanisms, cancer cells need to handle elevated levels of DNA damage and ensuing genomic instability in order to continue proliferating. How this is achieved is only partially understood. To advance our understanding of this response and to identify potentially druggable regulators, we screened the family of human F-box proteins (FBP) for effects on replication re-start under conditions of OIRS. FBPs function as interchangeable substrate recognition sub-units of the SKP1-Cullin1-FBP ubiquitin ligase complex. They are required for conferring substrate specificity to the complex and some FBPs have been attributed roles as oncogenes or tumor suppressors while the majority remain largely uncharacterized. Our screen revealed the relatively unknown FBP FBXL12 as crucial regulator for sustained proliferation and genomic integrity under conditions of cyclin E-induced replication stress. FBXL12-depleted cells exhibit excessive replication fork stalling, high levels of DNA damage signaling and spontaneous senescence in OIRS breast cancer model cell lines. Interestingly, the same effects are not manifest in untransformed cell lines. Furthermore, we found that FBXL12 interacts with central chromatin-associated components of the Fanconi anemia (FA)-BRCA signaling pathway, ubiquitylating and targeting them for proteasomal degradation, and thereby exerting its effects on stalled replication forks. The specific nature of FA-BRCA signaling regulation by FBXL12 as well as potential clinical implications for basal-like breast cancers will be discussed. Citation Format: Andrä Brunner, Henrik Johansson, Alexandros Kourtesakis, Juha Rantala, Charles Spruck, James Wohlschlegel, Janne Lehtiö, Olle Sangfelt. FBXL12 modulates Fanconi anaemia-BRCA signaling under conditions of oncogene-induced replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2371.