Abstract 3719: Docking analyses of miR-21 with RNA-binding proteins that interact with BRCA1

Abstract RNA binding proteins (RBPs) are key post-transcriptional regulators that predominantly control gene expression through RNA metabolism. Dysregulation of RBPs is implicated in therapy resistance of breast cancer and targeting key RBPs can be a promising therapeutic approach to reverse this resistance. However, the RBP-related mechanisms in breast cancer are complex, influencing the critical proteins involved in cellular DNA damage response (DDR) at one end and modulating the processing of primary miRNA (pri-miRNA) structures to precursor forms on the other end. Studies strongly demonstrated that a stress-responsive RBP, namely nucleolin (NCL) co-localizes with the tumor suppressor breast and ovarian cancer susceptibility gene (BRCA1) during DDR and regulates the expression of a specific subset of miRNAs (miR-21, miR-221, miR-222, and miR-103) that are causally involved in breast cancer initiation, progression, and drug resistance. Earlier we generated docking scenarios with this subset of miRNAs to demonstrate a role of NCL-RNA-binding domain (RBD) 3 and 4 playing a significant role in such interactions. We also identified a group of RBPs as common interactors of BRCA1 and NCL, namely heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), heterogeneous nuclear ribonucleoprotein D (HNRNPD), polyadenylate binding protein cytoplasmic 1(PABPC1), and TAR DNA-binding protein 43 (TDP-43). Interestingly, miR-21 is revealed as a known predicted target of this subset of RBPs. In this study, we therefore focus on modeling docking scenarios of miR-21 with these four RBPs and assessed NCL-binding to miR-21. In this study, we utilized complete RBD regions of these RBPs to predict models for RBP-miR-21 interactions, to highlight the conserved motifs participating in such an interaction. Next, we propose models of competitive versus synergistic binding of miR-21 with the different RBPs. The computational models generated in this study will provide key insights about the RBP- miR-21 interacting interfaces. Additionally, RBP-BRCA1 collaborations further provides insights about how miR-21 regulation by RBP play a role in defective DNA repair mechanism in breast cancer that could serve as potential for therapeutic intervention. Citation Format: Yelyzaveta Khayman, Shaneen Singh, Anjana Saxena. Docking analyses of miR-21 with RNA-binding proteins that interact with BRCA1 [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 3719.