Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability

Abstract Genetic polymorphisms in DNA damage repair and tumor suppressor genes have been associated with increasing the risk of several types of cancer. Analyses of putative functional single nucleotide polymorphisms (SNP) in such genes can greatly improve human health by guiding choice of therapeut...

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Autores principales:	Mahjerin Nasrin Reza, Nadim Ferdous, Md. Tabassum Hossain Emon, Md. Shariful Islam, A. K. M. Mohiuddin, Mohammad Uzzal Hossain
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/edb6a56ade834b879c60778e04c18f2b
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spelling	oai:doaj.org-article:edb6a56ade834b879c60778e04c18f2b2021-12-02T19:17:00ZPathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability10.1038/s41598-021-98547-y2045-2322https://doaj.org/article/edb6a56ade834b879c60778e04c18f2b2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98547-yhttps://doaj.org/toc/2045-2322Abstract Genetic polymorphisms in DNA damage repair and tumor suppressor genes have been associated with increasing the risk of several types of cancer. Analyses of putative functional single nucleotide polymorphisms (SNP) in such genes can greatly improve human health by guiding choice of therapeutics. In this study, we selected nine genes responsible for various cancer types for gene enrichment analysis and found that BRCA1, ATM, and TP53 were more enriched in connectivity. Therefore, we used different computational algorithms to classify the nonsynonymous SNPs which are deleterious to the structure and/or function of these three proteins. The present study showed that the major pathogenic variants (V1687G and V1736G of BRCA1, I2865T and V2906A of ATM, V216G and L194H of TP53) might have a greater impact on the destabilization of the proteins. To stabilize the high-risk SNPs, we performed mutation site-specific molecular docking analysis and validated using molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) studies. Additionally, SNPs of untranslated regions of these genes affecting miRNA binding were characterized. Hence, this study will assist in developing precision medicines for cancer types related to these polymorphisms.Mahjerin Nasrin RezaNadim FerdousMd. Tabassum Hossain EmonMd. Shariful IslamA. K. M. MohiuddinMohammad Uzzal HossainNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mahjerin Nasrin Reza Nadim Ferdous Md. Tabassum Hossain Emon Md. Shariful Islam A. K. M. Mohiuddin Mohammad Uzzal Hossain Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability
description	Abstract Genetic polymorphisms in DNA damage repair and tumor suppressor genes have been associated with increasing the risk of several types of cancer. Analyses of putative functional single nucleotide polymorphisms (SNP) in such genes can greatly improve human health by guiding choice of therapeutics. In this study, we selected nine genes responsible for various cancer types for gene enrichment analysis and found that BRCA1, ATM, and TP53 were more enriched in connectivity. Therefore, we used different computational algorithms to classify the nonsynonymous SNPs which are deleterious to the structure and/or function of these three proteins. The present study showed that the major pathogenic variants (V1687G and V1736G of BRCA1, I2865T and V2906A of ATM, V216G and L194H of TP53) might have a greater impact on the destabilization of the proteins. To stabilize the high-risk SNPs, we performed mutation site-specific molecular docking analysis and validated using molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) studies. Additionally, SNPs of untranslated regions of these genes affecting miRNA binding were characterized. Hence, this study will assist in developing precision medicines for cancer types related to these polymorphisms.
format	article
author	Mahjerin Nasrin Reza Nadim Ferdous Md. Tabassum Hossain Emon Md. Shariful Islam A. K. M. Mohiuddin Mohammad Uzzal Hossain
author_facet	Mahjerin Nasrin Reza Nadim Ferdous Md. Tabassum Hossain Emon Md. Shariful Islam A. K. M. Mohiuddin Mohammad Uzzal Hossain
author_sort	Mahjerin Nasrin Reza
title	Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability
title_short	Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability
title_full	Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability
title_fullStr	Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability
title_full_unstemmed	Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability
title_sort	pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/edb6a56ade834b879c60778e04c18f2b
work_keys_str_mv	AT mahjerinnasrinreza pathogenicgeneticvariantsfromhighlyconnectedcancersusceptibilitygenesconferthelossofstructuralstability AT nadimferdous pathogenicgeneticvariantsfromhighlyconnectedcancersusceptibilitygenesconferthelossofstructuralstability AT mdtabassumhossainemon pathogenicgeneticvariantsfromhighlyconnectedcancersusceptibilitygenesconferthelossofstructuralstability AT mdsharifulislam pathogenicgeneticvariantsfromhighlyconnectedcancersusceptibilitygenesconferthelossofstructuralstability AT akmmohiuddin pathogenicgeneticvariantsfromhighlyconnectedcancersusceptibilitygenesconferthelossofstructuralstability AT mohammaduzzalhossain pathogenicgeneticvariantsfromhighlyconnectedcancersusceptibilitygenesconferthelossofstructuralstability
_version_	1718376946546507776

Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability

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