Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessment
BackgroundThe RAD50 gene on chromosome 5q3.11 plays an important role in the MRN (Mre11–Rad50–Nbs1) complex. This complex orchestrates cellular responses to the DNA double-strand breaks (DSBs) through several pathways for genome stability. This study aims to investigate the functional impact of non-...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-03-01
|
| Series: | Frontiers in Bioinformatics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fbinf.2025.1535482/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850098021368332288 |
|---|---|
| author | Samina Malik Mirza Jawad Ul Hasnain Mirza Jawad Ul Hasnain Gul Zaib Haleema Saadia Arif Malik Ayesha Zahid |
| author_facet | Samina Malik Mirza Jawad Ul Hasnain Mirza Jawad Ul Hasnain Gul Zaib Haleema Saadia Arif Malik Ayesha Zahid |
| author_sort | Samina Malik |
| collection | DOAJ |
| description | BackgroundThe RAD50 gene on chromosome 5q3.11 plays an important role in the MRN (Mre11–Rad50–Nbs1) complex. This complex orchestrates cellular responses to the DNA double-strand breaks (DSBs) through several pathways for genome stability. This study aims to investigate the functional impact of non-synonymous single-nucleotide polymorphisms (nsSNPs) in RAD50 (a breast cancer-associated gene) and focuses on their consequences on protein structure and interaction within the MRN complex.MethodsA total of 1,806 nsSNPs were retrieved and subjected to variant analysis using a set 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 secondary structure prediction, whereas AlphaFold, RoseTTAFold, and I-TASSER were used for protein structure prediction. The 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.ResultsA subset of pathogenic and disease-associated nsSNPs in the RAD50 gene altered the 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.ConclusionThe study discloses the normative impact of RAD50 mutations on the pathophysiology of breast cancer. It can provide the basis to treat RAD50 mutation-deficient cells. |
| format | Article |
| id | doaj-art-852769de27b14aa986cf57bcd63aac4e |
| institution | DOAJ |
| issn | 2673-7647 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioinformatics |
| spelling | doaj-art-852769de27b14aa986cf57bcd63aac4e2025-08-20T02:40:48ZengFrontiers Media S.A.Frontiers in Bioinformatics2673-76472025-03-01510.3389/fbinf.2025.15354821535482Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessmentSamina Malik0Mirza Jawad Ul Hasnain1Mirza Jawad Ul Hasnain2Gul Zaib3Haleema Saadia4Arif Malik5Ayesha Zahid6University College of Medicine and Dentistry, The University of Lahore, IMBB, UOL, Lahore, PakistanDepartment of Biological Sciences, Virtual University of Pakistan, Islamabad, PakistanCenter for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaSchool of Pain and Regenerative Medicine, The University of Lahore, IMBB, UOL, Lahore, PakistanSchool of Pain and Regenerative Medicine, The University of Lahore, IMBB, UOL, Lahore, PakistanSchool of Pain and Regenerative Medicine, The University of Lahore, IMBB, UOL, Lahore, PakistanSchool of Pain and Regenerative Medicine, The University of Lahore, IMBB, UOL, Lahore, PakistanBackgroundThe RAD50 gene on chromosome 5q3.11 plays an important role in the MRN (Mre11–Rad50–Nbs1) complex. This complex orchestrates cellular responses to the DNA double-strand breaks (DSBs) through several pathways for genome stability. This study aims to investigate the functional impact of non-synonymous single-nucleotide polymorphisms (nsSNPs) in RAD50 (a breast cancer-associated gene) and focuses on their consequences on protein structure and interaction within the MRN complex.MethodsA total of 1,806 nsSNPs were retrieved and subjected to variant analysis using a set 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 secondary structure prediction, whereas AlphaFold, RoseTTAFold, and I-TASSER were used for protein structure prediction. The 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.ResultsA subset of pathogenic and disease-associated nsSNPs in the RAD50 gene altered the 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.ConclusionThe study discloses the normative impact of RAD50 mutations on the pathophysiology of breast cancer. It can provide the basis to treat RAD50 mutation-deficient cells.https://www.frontiersin.org/articles/10.3389/fbinf.2025.1535482/fullbreast cancerRad50MRE11Adockingsimulation |
| spellingShingle | Samina Malik Mirza Jawad Ul Hasnain Mirza Jawad Ul Hasnain Gul Zaib Haleema Saadia Arif Malik Ayesha Zahid Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessment Frontiers in Bioinformatics breast cancer Rad50 MRE11A docking simulation |
| title | Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessment |
| title_full | Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessment |
| title_fullStr | Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessment |
| title_full_unstemmed | Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessment |
| title_short | Comprehensive structural and functional analyses of RAD50 nsSNPs: from prediction to impact assessment |
| title_sort | comprehensive structural and functional analyses of rad50 nssnps from prediction to impact assessment |
| topic | breast cancer Rad50 MRE11A docking simulation |
| url | https://www.frontiersin.org/articles/10.3389/fbinf.2025.1535482/full |
| work_keys_str_mv | AT saminamalik comprehensivestructuralandfunctionalanalysesofrad50nssnpsfrompredictiontoimpactassessment AT mirzajawadulhasnain comprehensivestructuralandfunctionalanalysesofrad50nssnpsfrompredictiontoimpactassessment AT mirzajawadulhasnain comprehensivestructuralandfunctionalanalysesofrad50nssnpsfrompredictiontoimpactassessment AT gulzaib comprehensivestructuralandfunctionalanalysesofrad50nssnpsfrompredictiontoimpactassessment AT haleemasaadia comprehensivestructuralandfunctionalanalysesofrad50nssnpsfrompredictiontoimpactassessment AT arifmalik comprehensivestructuralandfunctionalanalysesofrad50nssnpsfrompredictiontoimpactassessment AT ayeshazahid comprehensivestructuralandfunctionalanalysesofrad50nssnpsfrompredictiontoimpactassessment |