Abstract 3711: An RNA-binding phosphoprotein twist with BRCT domains in DNA damage repair: computational modeling of nucleolin

Abstract Nucleolin (NCL), an RNA binding protein (RBP), and BRCA1, a tumor suppressor protein linked to breast and ovarian cancer susceptibility, colocalize at the sites of DNA damage and collaborate in homologous DNA repair pathways. Even so, the underlying mechanism where NCL and BRCA1 function together during DNA damage repair (DDR) remains unexplored. We utilized in silico approaches to unveil and characterize the shared interactome of BRCA1 and NCL. Our analysis revealed 49 common proteins interacting with BRCA1 and NCL, potentially influencing their functions. These proteins were systematically categorized into five distinct Gene Ontology (GO) annotation classes: DNA repair, RNA-binding, chromatin remodeling, DNA damage, and cell cycle regulation. Here, we predict interaction scenarios between full-length NCL and five BRCT-containing proteins crucial for DNA repair: BRCA1, MDC1, NBN, PARP1, and TP53BP1, to provide molecular insights into the interface. We strongly predict that the N-terminal acidic region of NCL which is also a site of several CK2 and CDK1 phosphorylation sites is involved in interaction with these five BRCT-containing proteins. Our computational models predict that RNA binding domains (RBDs) of NCL remain free to bind RNA or DNA, potentially facilitating its role in DDR. We further present the mutational landscape of the BRCT regions of these five proteins using the COSMIC database and identify the sites that might affect their interactions with NCL. Identifying the common interactome that associates with NCL and BRCA1 duo will facilitate our understanding of the intricate molecular interplay during the DDR. These protein-protein interactions potentially provide targetable interfaces, especially to combat aggressive triple-negative breast cancer where the DNA-repair pathway is predominantly deregulated. Citation Format: Nitu Farhin, Andriele S. Eichner, Anjana Saxena, Shaneen Singh. An RNA-binding phosphoprotein twist with BRCT domains in DNA damage repair: computational modeling of nucleolin [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 3711.