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

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.

Contributors

Firoz Ahmed:

ORCID: http://orcid.org/0000-0003-4702-5144

[e-mail]

Mohammad Sarwar Jamal: [e-mail]

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 23 July 2020

Publication date PMC-release: 23 July 2020

Publication date Collection: 2020

Volume: 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

Publisher ID: 69033

DOI: 10.1038/s41598-020-69033-8

PMC ID: 7378827

Copyright statement: © The Author(s) 2020

License:

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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