title: Functional and Structural Consequences of Damaging Single Nucleotide Polymorphisms in Human Prostate Cancer Predisposition Gene RNASEL.
abstract: A commonly diagnosed cancer, prostate cancer (PrCa), is being regulated by the gene RNASEL previously known as PRCA1 codes for ribonuclease L which is an integral part of interferon regulated system that mediates antiviral and antiproliferative role of the interferons. Both somatic and germline mutations have been implicated to cause prostate cancer. With an array of available Single Nucleotide Polymorphism data on dbSNP this study is designed to sort out functional SNPs in RNASEL by implementing different authentic computational tools such as SIFT, PolyPhen, SNPs&GO, Fathmm, ConSurf, UTRScan, PDBsum, Tm-Align, I-Mutant, and Project HOPE for functional and structural assessment, solvent accessibility, molecular dynamics, and energy minimization study. Among 794 RNASEL SNP entries 124 SNPs were found nonsynonymous from which SIFT predicted 13 nsSNPs as nontolerable whereas PolyPhen-2 predicted 28. SNPs found on the 3' and 5' UTR were also assessed. By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L. The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins. Expasy-ProSit tool defined the mutations to be situated in the functional domains of the protein. Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H). As such studies involving polymorphisms of RNASEL were none to be found, the results of the current study would certainly be helpful in future prospects concerning prostate cancer in males.
authors.affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh.
authors.forename: Amit
authors.initials: A
authors.lastname: Datta
authors.affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh.
authors.forename: Md Habibul Hasan
authors.initials: MH
authors.lastname: Mazumder
authors.affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh.
authors.forename: Afrin Sultana
authors.initials: AS
authors.lastname: Chowdhury
authors.affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong 4331, Bangladesh.
authors.forename: Md Anayet
authors.initials: MA
authors.lastname: Hasan
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000596:Amino Acids / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D030541:Databases, Genetic; D004722:Endoribonucleases / Q000737:chemistry* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012307:Risk Factors; D012984:Software; D013816:Thermodynamics
chemical_list: D020121:5' Untranslated Regions; D000596:Amino Acids; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease