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Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome

The human gene MUTYH codes for a DNA glycosylase involved in the repair of oxidative DNA damage. Faulty MUTYH protein activity causes the accumulation of G→T transversions due to unrepaired 8-oxoG:A mismatches. MUTYH germ-line mutations in humans are linked with a recessive form of Familial Adenomat...

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Autores principales: Abduljaleel, Zainularifeen, Athar, Mohammad, Al-Allaf, Faisal A., Al-Dehlawi, Saied, Vazquez, Jose R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: KeAi Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012779/
https://www.ncbi.nlm.nih.gov/pubmed/32072083
http://dx.doi.org/10.1016/j.ncrna.2019.11.005
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author Abduljaleel, Zainularifeen
Athar, Mohammad
Al-Allaf, Faisal A.
Al-Dehlawi, Saied
Vazquez, Jose R.
author_facet Abduljaleel, Zainularifeen
Athar, Mohammad
Al-Allaf, Faisal A.
Al-Dehlawi, Saied
Vazquez, Jose R.
author_sort Abduljaleel, Zainularifeen
collection PubMed
description The human gene MUTYH codes for a DNA glycosylase involved in the repair of oxidative DNA damage. Faulty MUTYH protein activity causes the accumulation of G→T transversions due to unrepaired 8-oxoG:A mismatches. MUTYH germ-line mutations in humans are linked with a recessive form of Familial Adenomatous Polyposis (FAP) and colorectal cancer predisposition. We studied the repair capacity of variants identified in MUTYH-associated polyposis (MAP) patients. MAP is inherited in an autosomal recessive type due to mutations in MUTYH (Y165C, G382D, P54S, A22V, Q63R, G45D, S136P and N43S), indicating that both copies of the gene become inactivated. However, the parents of an individual with an autosomal recessive condition may serve as carriers, each harboring one copy of the mutated gene without showing signs or symptoms of MAP. Six protein partners have been associated with MUTYH, four via direct physical interactions, namely, hMSH6, hPCNA, hRPA1, and hAPEX1. We examined, for the first time, specific interactions of these protein partners with MAP-associated MUTYH mutants using molecular dynamics simulations. The approach provided tools for exploration of the conformational energy landscape accessible to protein partners. The investigation also determined the impact before and after energy minimization of protein-protein interactions and binding affinities of MUTYH wild type and mutant forms, as well as the interactions with other proteins. Taken together, this study provided new insights into the role of MUTYH and its interacting proteins in MAP.
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spelling pubmed-70127792020-02-18 Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome Abduljaleel, Zainularifeen Athar, Mohammad Al-Allaf, Faisal A. Al-Dehlawi, Saied Vazquez, Jose R. Noncoding RNA Res Article The human gene MUTYH codes for a DNA glycosylase involved in the repair of oxidative DNA damage. Faulty MUTYH protein activity causes the accumulation of G→T transversions due to unrepaired 8-oxoG:A mismatches. MUTYH germ-line mutations in humans are linked with a recessive form of Familial Adenomatous Polyposis (FAP) and colorectal cancer predisposition. We studied the repair capacity of variants identified in MUTYH-associated polyposis (MAP) patients. MAP is inherited in an autosomal recessive type due to mutations in MUTYH (Y165C, G382D, P54S, A22V, Q63R, G45D, S136P and N43S), indicating that both copies of the gene become inactivated. However, the parents of an individual with an autosomal recessive condition may serve as carriers, each harboring one copy of the mutated gene without showing signs or symptoms of MAP. Six protein partners have been associated with MUTYH, four via direct physical interactions, namely, hMSH6, hPCNA, hRPA1, and hAPEX1. We examined, for the first time, specific interactions of these protein partners with MAP-associated MUTYH mutants using molecular dynamics simulations. The approach provided tools for exploration of the conformational energy landscape accessible to protein partners. The investigation also determined the impact before and after energy minimization of protein-protein interactions and binding affinities of MUTYH wild type and mutant forms, as well as the interactions with other proteins. Taken together, this study provided new insights into the role of MUTYH and its interacting proteins in MAP. KeAi Publishing 2019-12-04 /pmc/articles/PMC7012779/ /pubmed/32072083 http://dx.doi.org/10.1016/j.ncrna.2019.11.005 Text en © 2020 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Abduljaleel, Zainularifeen
Athar, Mohammad
Al-Allaf, Faisal A.
Al-Dehlawi, Saied
Vazquez, Jose R.
Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
title Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
title_full Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
title_fullStr Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
title_full_unstemmed Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
title_short Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
title_sort association of functional variants and protein-to-protein physical interactions of human muty homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012779/
https://www.ncbi.nlm.nih.gov/pubmed/32072083
http://dx.doi.org/10.1016/j.ncrna.2019.11.005
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