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      Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach

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          Abstract

          The BLM helicase protein plays a vital role in DNA replication and the maintenance of genomic integrity. Variation in the BLM helicase gene resulted in defects in the DNA repair mechanism and was reported to be associated with Bloom syndrome (BS) and cancer. Despite extensive investigation of helicase proteins in humans, no attempt has previously been made to comprehensively analyse the single nucleotide polymorphism (SNPs) of the BLM gene. In this study, a comprehensive analysis of SNPs on the BLM gene was performed to identify, characterize and validate the pathogenic SNPs using computational approaches. We obtained SNP data from the dbSNP database version 150 and mapped these data to the genomic coordinates of the “NM_000057.3” transcript expressing BLM helicase (P54132). There were 607 SNPs mapped to missense, 29 SNPs mapped to nonsense, and 19 SNPs mapped to 3′-UTR regions. Initially, we used many consensus tools of SIFT, PROVEAN, Condel, and PolyPhen-2, which together increased the accuracy of prediction and identified 18 highly pathogenic non-synonymous SNPs (nsSNPs) out of 607 SNPs. Subsequently, these 18 high-confidence pathogenic nsSNPs were analysed for BLM protein stability, structure–function relationships and disease associations using various bioinformatics tools. These 18 mutants of the BLM protein along with the native protein were further investigated using molecular dynamics simulations to examine the structural consequences of the mutations, which might reveal their malfunction and contribution to disease. In addition, 28 SNPs were predicted as “stop gained” nonsense SNPs and one SNP was predicted as “start lost”. Two SNPs in the 3′UTR were found to abolish miRNA binding and thus may enhance the expression of BLM. Interestingly, we found that BLM mRNA overexpression is associated with different types of cancers. Further investigation showed that the dysregulation of BLM is associated with poor overall survival (OS) for lung and gastric cancer patients and hence led to the conclusion that BLM has the potential to be used as an important prognostic marker for the detection of lung and gastric cancer.

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          Most cited references 89

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          Human non-synonymous SNPs: server and survey.

           V. Ramensky (2002)
          Human single nucleotide polymorphisms (SNPs) represent the most frequent type of human population DNA variation. One of the main goals of SNP research is to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases. Non-synonymous coding SNPs (nsSNPs) comprise a group of SNPs that, together with SNPs in regulatory regions, are believed to have the highest impact on phenotype. Here we present a World Wide Web server to predict the effect of an nsSNP on protein structure and function. The prediction method enabled analysis of the publicly available SNP database HGVbase, which gave rise to a dataset of nsSNPs with predicted functionality. The dataset was further used to compare the effect of various structural and functional characteristics of amino acid substitutions responsible for phenotypic display of nsSNPs. We also studied the dependence of selective pressure on the structural and functional properties of proteins. We found that in our dataset the selection pressure against deleterious SNPs depends on the molecular function of the protein, although it is insensitive to several other protein features considered. The strongest selective pressure was detected for proteins involved in transcription regulation.
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            The Bloom's syndrome helicase suppresses crossing over during homologous recombination.

            Mutations in BLM, which encodes a RecQ helicase, give rise to Bloom's syndrome, a disorder associated with cancer predisposition and genomic instability. A defining feature of Bloom's syndrome is an elevated frequency of sister chromatid exchanges. These arise from crossing over of chromatid arms during homologous recombination, a ubiquitous process that exists to repair DNA double-stranded breaks and damaged replication forks. Whereas crossing over is required in meiosis, in mitotic cells it can be associated with detrimental loss of heterozygosity. BLM forms an evolutionarily conserved complex with human topoisomerase IIIalpha (hTOPO IIIalpha), which can break and rejoin DNA to alter its topology. Inactivation of homologues of either protein leads to hyper-recombination in unicellular organisms. Here, we show that BLM and hTOPO IIIalpha together effect the resolution of a recombination intermediate containing a double Holliday junction. The mechanism, which we term double-junction dissolution, is distinct from classical Holliday junction resolution and prevents exchange of flanking sequences. Loss of such an activity explains many of the cellular phenotypes of Bloom's syndrome. These results have wider implications for our understanding of the process of homologous recombination and the mechanisms that exist to prevent tumorigenesis.
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              The Bloom's syndrome gene product is homologous to RecQ helicases.

               J German,  Zhen Ye,  T Ye (1995)
              The Bloom's syndrome (BS) gene, BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping. In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence of chain-terminating mutations in the candidate gene in persons with BS proved that it was BLM.
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                Author and article information

                Contributors
                fahmed1@uj.edu.sa
                Sarwar4u@gmail.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                23 July 2020
                23 July 2020
                2020
                : 10
                Affiliations
                [1 ]ISNI 0000 0001 0619 1117, GRID grid.412125.1, Department of Biochemistry, Faculty of Science, Stem Cells Unit, King Fahd Medical Research Center, , King Abdulaziz University, ; Jeddah, 21589 Saudi Arabia
                [2 ]ISNI 0000 0004 0376 4727, GRID grid.7273.1, Aston Medical Research Institute, Aston Medical School, , Aston University, ; Birmingham, B4 7ET UK
                [3 ]GRID grid.460099.2, Department of Biochemistry, College of Science, , University of Jeddah, ; Jeddah, 21589 Saudi Arabia
                [4 ]GRID grid.460099.2, University of Jeddah Centre for Scientific and Medical Research (UJ-CSMR), University of Jeddah, ; Jeddah, 21589 Saudi Arabia
                [5 ]ISNI 0000 0004 0406 1521, GRID grid.458435.b, Department of Chemical Sciences, , Indian Institute of Science Education and Research (IISER), ; Mohali, India
                [6 ]ISNI 0000 0001 0619 1117, GRID grid.412125.1, King Fahd Medical Research Center, , King Abdulaziz University, ; Jeddah, Saudi Arabia
                [7 ]ISNI 0000 0001 0619 1117, GRID grid.412125.1, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, , King Abdulaziz University, ; Jeddah, Saudi Arabia
                [8 ]ISNI 0000 0004 0498 8255, GRID grid.411818.5, Department of Computer Science, , Jamia Millia Islamia, ; New Delhi, Delhi India
                [9 ]GRID grid.460099.2, Department of Biology, College of Science, , University of Jeddah, ; Jeddah, 21589 Saudi Arabia
                [10 ]ISNI 0000 0001 2191 4301, GRID grid.415310.2, Department of Genetics, Research Center, , King Faisal Specialist Hospital, and Research Center, ; MBC-03, PO Box 3354, Riyadh, 11211 Saudi Arabia
                [11 ]ISNI 0000 0004 1754 9358, GRID grid.412892.4, Department of Biology, Faculty of Science, , University of Taibah, ; Medinah, Saudi Arabia
                [12 ]GRID grid.449051.d, Department of Medical Laboratories, Central Biosciences Research Laboratories, College of Science in Al Zulfi, , Majmaah University, ; Al Majma’ah, Saudi Arabia
                [13 ]ISNI 0000 0001 0619 1117, GRID grid.412125.1, Department of Biochemistry, Cancer Metabolism and Epigenetic Unit, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, , King Abdulaziz University, ; Jeddah, Saudi Arabia
                [14 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Integrative Biosciences Center, , Wayne State University, ; Detroit, MI 48202 USA
                Article
                69033
                10.1038/s41598-020-69033-8
                7378827
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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