Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis
ObjectivesUnlike other diseases, cancer is not just a genome disease but should broadly be viewed as a disease of the cellular machinery. Therefore, integrative multifaceted approaches are crucial to understanding the complex nature of cancer biology. Bcl-2 (B-cell lymphoma 2), encoded by the human...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2024.1502152/full |
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| author | Ghazi Elamin Ghazi Elamin Zhichao Zhang Depika Dwarka Kabange Kasumbwe John Mellem Nompumelelo P. Mkhwanazi Paradise Madlala Paradise Madlala Mahmoud E. S. Soliman |
| author_facet | Ghazi Elamin Ghazi Elamin Zhichao Zhang Depika Dwarka Kabange Kasumbwe John Mellem Nompumelelo P. Mkhwanazi Paradise Madlala Paradise Madlala Mahmoud E. S. Soliman |
| author_sort | Ghazi Elamin |
| collection | DOAJ |
| description | ObjectivesUnlike other diseases, cancer is not just a genome disease but should broadly be viewed as a disease of the cellular machinery. Therefore, integrative multifaceted approaches are crucial to understanding the complex nature of cancer biology. Bcl-2 (B-cell lymphoma 2), encoded by the human Bcl-2 gene, is a critical anti-apoptotic protein that regulates cell death pathways, primarily by inhibiting apoptosis. It plays a pivotal role in maintaining cellular homeostasis by preventing premature or excessive cell death. Genetic variations and dysregulation of Bcl-2 are particularly significant in cancer, as they disrupt the normal apoptotic machinery, enabling cancer cells to evade programmed cell death. Single nucleotide polymorphisms (SNPs) are considered viable diagnostic and therapeutic biomarkers for various cancers. Therefore, this study explores the association between SNPs in Bcl-2 and the structural, functional, protein-protein interactions (PPIs), drug binding and dynamic characteristics.MethodsComprehensive cross-validated bioinformatics tools and molecular dynamics (MD) simulations. Multiple sequence, genetic, structural and disease phenotype analyses were applied in this study.ResultsAnalysis revealed that out of 130 mutations, approximately 8.5% of these mutations were classified as pathogenic. Furthermore, two particular variants, namely, Bcl-2G101V and Bcl-2F104L, were found to be the most deleterious across all analyses. Following 500 ns, MD simulations showed that these mutations caused a significant distortion in the protein conformational, protein-protein interactions (PPIs), and drug binding landscape compared to Bcl-2WT.ConclusionDespite being a predictive study, the findings presented in this report would offer a perspective insight for further experimental investigation, rational drug design, and cancer gene therapy. |
| format | Article |
| id | doaj-art-bb7a6a8e42c64f71a82a0f1dc6e0da1f |
| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj-art-bb7a6a8e42c64f71a82a0f1dc6e0da1f2025-01-22T09:16:05ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-01-011510.3389/fgene.2024.15021521502152Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesisGhazi Elamin0Ghazi Elamin1Zhichao Zhang2Depika Dwarka3Kabange Kasumbwe4John Mellem5Nompumelelo P. Mkhwanazi6Paradise Madlala7Paradise Madlala8Mahmoud E. S. Soliman9Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, South AfricaDepartment of Pharmaceutical Chemistry, College of Pharmacy, Karary University, Khartoum, SudanSchool of Chemistry, Dalian University of Technology, Dalian, Liaoning, ChinaEzintsha, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South AfricaBiotechnology and Food Science, Durban University of Technology, Durban, South AfricaBiotechnology and Food Science, Durban University of Technology, Durban, South AfricaHIV Pathogenesis Programme, School of Laboratory Medicine and Medical Science, The Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaHIV Pathogenesis Programme, School of Laboratory Medicine and Medical Science, The Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaSchool of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South AfricaMolecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, South AfricaObjectivesUnlike other diseases, cancer is not just a genome disease but should broadly be viewed as a disease of the cellular machinery. Therefore, integrative multifaceted approaches are crucial to understanding the complex nature of cancer biology. Bcl-2 (B-cell lymphoma 2), encoded by the human Bcl-2 gene, is a critical anti-apoptotic protein that regulates cell death pathways, primarily by inhibiting apoptosis. It plays a pivotal role in maintaining cellular homeostasis by preventing premature or excessive cell death. Genetic variations and dysregulation of Bcl-2 are particularly significant in cancer, as they disrupt the normal apoptotic machinery, enabling cancer cells to evade programmed cell death. Single nucleotide polymorphisms (SNPs) are considered viable diagnostic and therapeutic biomarkers for various cancers. Therefore, this study explores the association between SNPs in Bcl-2 and the structural, functional, protein-protein interactions (PPIs), drug binding and dynamic characteristics.MethodsComprehensive cross-validated bioinformatics tools and molecular dynamics (MD) simulations. Multiple sequence, genetic, structural and disease phenotype analyses were applied in this study.ResultsAnalysis revealed that out of 130 mutations, approximately 8.5% of these mutations were classified as pathogenic. Furthermore, two particular variants, namely, Bcl-2G101V and Bcl-2F104L, were found to be the most deleterious across all analyses. Following 500 ns, MD simulations showed that these mutations caused a significant distortion in the protein conformational, protein-protein interactions (PPIs), and drug binding landscape compared to Bcl-2WT.ConclusionDespite being a predictive study, the findings presented in this report would offer a perspective insight for further experimental investigation, rational drug design, and cancer gene therapy.https://www.frontiersin.org/articles/10.3389/fgene.2024.1502152/fullBcl-2nsSNPsmutationsgenomic analysesmolecular dynamics simulations |
| spellingShingle | Ghazi Elamin Ghazi Elamin Zhichao Zhang Depika Dwarka Kabange Kasumbwe John Mellem Nompumelelo P. Mkhwanazi Paradise Madlala Paradise Madlala Mahmoud E. S. Soliman Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis Frontiers in Genetics Bcl-2 nsSNPs mutations genomic analyses molecular dynamics simulations |
| title | Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis |
| title_full | Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis |
| title_fullStr | Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis |
| title_full_unstemmed | Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis |
| title_short | Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis |
| title_sort | integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of bcl 2 gene on the apoptotic machinery and implications in carcinogenesis |
| topic | Bcl-2 nsSNPs mutations genomic analyses molecular dynamics simulations |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1502152/full |
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