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ORIGINAL RESEARCH article
Front. Bioinform.
Sec. Drug Discovery in Bioinformatics
Volume 5 - 2025 | doi: 10.3389/fbinf.2025.1535482
Comprehensive Structural and Functional Analysis of RAD50 nsSNPs: From Prediction to Impact Assessment
Provisionally accepted- 1 University College of Medicine and Dentistry, University of Lahore, Lahore, Punjab, Pakistan
- 2 Department of Biotechnology, Virtual University of Pakistan, Lahore, Punjab, Pakistan
- 3 School of Pain and Regenerative Medicine, University of Lahore, Lahore, Pakistan
Background: The RAD50 gene on chromosome 5q3.11, plays an important role in the MRN (Mre11-Rad50-Nbs1). This complex orchestrates cellular responses to the DNA double-strand breaks (DSBs) through several pathways for genome stability. This study aimed to investigate the functional impact of non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in the RAD50 (a breast cancer-associated gene). It is focused on their consequences on protein structure and interaction within the MRN complex.Methods: A total of 1806 nsSNPs were retrieved and subjected to variant analysis using a suite of computational tools, and Consurf. Pathogenicity and protein stability criteria were established based on specific tools. Highly conserved damaging nsSNPs were prioritized for the structural analysis. GOR-IV was used for the secondary structure prediction whereas, Alpha Fold, Rosetta Fold, and I-TASSER were used for the protein structure prediction. Docking of RAD50-Mre11A complexes was performed using HADDOCK to assess the impact of nsSNPs on protein-protein interactions. Molecular dynamic simulation was performed to verify the role of mutants in molecular docking analysis.Results: A subset of pathogenic and disease-associated nsSNPs in the RAD50 gene that led to altering protein stability and interactions with the Mre11A protein. Substantial alterations in the interacting profiles of mutants (A73P, V117F, L518P, L1092R, N1144S, and A1209T) suggest potential implications for DNA repair mechanisms and genome stability.The study discloses the normative impact of RAD50 mutations on pathophysiology of breast cancer. It can provide the basis to treat RAD50 mutation-deficient cells.
Keywords: Name and designation: Gul Zaib, Lecturer Name and designation: Haleema Saadia, Research Associate Breast Cancer, Rad50, MRE11A, Docking, simulation
Received: 27 Nov 2024; Accepted: 24 Feb 2025.
Copyright: © 2025 Malik, Jawad Ul Hasnain, Zaib, Saadia, Malik and Zahid. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Gul Zaib, School of Pain and Regenerative Medicine, University of Lahore, Lahore, Pakistan
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