Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2
More than 4,000 single nucleotide polymorphisms (SNP) variants have been identified in the human ZFP36L2 gene, however only a few have been studied in the context of protein function. The tandem zinc finger domain of ZFP36L2, an RNA binding protein, is the functional domain that binds to its target...
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Taylor & Francis Group
2025-12-01
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| Series: | RNA Biology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15476286.2024.2437590 |
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| author | Betül Akçeşme Hilal Hekimoğlu Venkat R. Chirasani Şeyma İş Habibe Nur Atmaca Justin M. Waldern Silvia B.V. Ramos |
| author_facet | Betül Akçeşme Hilal Hekimoğlu Venkat R. Chirasani Şeyma İş Habibe Nur Atmaca Justin M. Waldern Silvia B.V. Ramos |
| author_sort | Betül Akçeşme |
| collection | DOAJ |
| description | More than 4,000 single nucleotide polymorphisms (SNP) variants have been identified in the human ZFP36L2 gene, however only a few have been studied in the context of protein function. The tandem zinc finger domain of ZFP36L2, an RNA binding protein, is the functional domain that binds to its target mRNAs. This protein/RNA interaction triggers mRNA degradation, controlling gene expression. We identified 32 non-synonymous SNPs (nsSNPs) in the tandem zinc finger domain of ZFP36L2 that could have possible deleterious impacts in humans. Using different bioinformatic strategies, we prioritized five among these 32 nsSNPs, namely rs375096815, rs1183688047, rs1214015428, rs1215671792 and rs920398592 to be validated. When we experimentally tested the functionality of these protein variants using gel shift assays, all five (Y154H, R160W, R184C, G204D, and C206F) resulted in a dramatic reduction in RNA binding compared to the WT protein. To understand the mechanistic effect of these variants on the protein/RNA interaction, we employed DUET, DynaMut and PyMOL to investigate structural changes in the protein. Additionally, we conducted Molecular Docking and Molecular Dynamics Simulations to fine tune the active behaviour of this biomolecular system at an atomic level. Our results propose atomic explanations for the impact of each of these five genetic variants identified. |
| format | Article |
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| institution | OA Journals |
| issn | 1547-6286 1555-8584 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
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| series | RNA Biology |
| spelling | doaj-art-1dc6d4e4013e40cd83affe11976995082025-08-20T01:58:51ZengTaylor & Francis GroupRNA Biology1547-62861555-85842025-12-0122111510.1080/15476286.2024.2437590Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2Betül Akçeşme0Hilal Hekimoğlu1Venkat R. Chirasani2Şeyma İş3Habibe Nur Atmaca4Justin M. Waldern5Silvia B.V. Ramos6Program of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Ilidža/Sarajevo, Bosnia and HerzegovinaInstitute of Health Sciences, İstanbul University, Fatih/İstanbul, TurkeyBiochemistry and Biophysics Department, School of Medicine, University of North Carolina, Chapel Hill, NC, USAHamidiye School of Medicine, Department of Basic Medical Sciences, Division of Medical Biology, University of Health Sciences, Üsküdar/İstanbul, TurkeyDepartment of Medical Biology, Faculty of Medicine, Ondokuz Mayıs University, Atakum/Samsun, TurkeyBiology Department, University of North Carolina, Chapel Hill, NC, USABiochemistry and Biophysics Department, School of Medicine, University of North Carolina, Chapel Hill, NC, USAMore than 4,000 single nucleotide polymorphisms (SNP) variants have been identified in the human ZFP36L2 gene, however only a few have been studied in the context of protein function. The tandem zinc finger domain of ZFP36L2, an RNA binding protein, is the functional domain that binds to its target mRNAs. This protein/RNA interaction triggers mRNA degradation, controlling gene expression. We identified 32 non-synonymous SNPs (nsSNPs) in the tandem zinc finger domain of ZFP36L2 that could have possible deleterious impacts in humans. Using different bioinformatic strategies, we prioritized five among these 32 nsSNPs, namely rs375096815, rs1183688047, rs1214015428, rs1215671792 and rs920398592 to be validated. When we experimentally tested the functionality of these protein variants using gel shift assays, all five (Y154H, R160W, R184C, G204D, and C206F) resulted in a dramatic reduction in RNA binding compared to the WT protein. To understand the mechanistic effect of these variants on the protein/RNA interaction, we employed DUET, DynaMut and PyMOL to investigate structural changes in the protein. Additionally, we conducted Molecular Docking and Molecular Dynamics Simulations to fine tune the active behaviour of this biomolecular system at an atomic level. Our results propose atomic explanations for the impact of each of these five genetic variants identified.https://www.tandfonline.com/doi/10.1080/15476286.2024.2437590Zinc finger protein 36 like 2non-synonymous single nucleotide polymorphisms (nsSNPs)deleterious effectRNA binding proteinAdenine Uridine Rich Elements (AREs) |
| spellingShingle | Betül Akçeşme Hilal Hekimoğlu Venkat R. Chirasani Şeyma İş Habibe Nur Atmaca Justin M. Waldern Silvia B.V. Ramos Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2 RNA Biology Zinc finger protein 36 like 2 non-synonymous single nucleotide polymorphisms (nsSNPs) deleterious effect RNA binding protein Adenine Uridine Rich Elements (AREs) |
| title | Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2 |
| title_full | Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2 |
| title_fullStr | Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2 |
| title_full_unstemmed | Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2 |
| title_short | Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2 |
| title_sort | identification of deleterious non synonymous single nucleotide polymorphisms in the mrna decay activator zfp36l2 |
| topic | Zinc finger protein 36 like 2 non-synonymous single nucleotide polymorphisms (nsSNPs) deleterious effect RNA binding protein Adenine Uridine Rich Elements (AREs) |
| url | https://www.tandfonline.com/doi/10.1080/15476286.2024.2437590 |
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