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Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma

The human hMYH and NEIL1 genes encode DNA glycosylases involved in repair of oxidative base damage and mutations in these genes are associated with certain cancers. Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease characterized by inflammatory destruction of the biliary tree...

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Autores principales: Forsbring, Monika, Vik, Erik S., Dalhus, Bjørn, Karlsen, Tom H., Bergquist, Annika, Schrumpf, Erik, Bjørås, Magnar, Boberg, Kirsten M., Alseth, Ingrun
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704287/
https://www.ncbi.nlm.nih.gov/pubmed/19443904
http://dx.doi.org/10.1093/carcin/bgp118
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author Forsbring, Monika
Vik, Erik S.
Dalhus, Bjørn
Karlsen, Tom H.
Bergquist, Annika
Schrumpf, Erik
Bjørås, Magnar
Boberg, Kirsten M.
Alseth, Ingrun
author_facet Forsbring, Monika
Vik, Erik S.
Dalhus, Bjørn
Karlsen, Tom H.
Bergquist, Annika
Schrumpf, Erik
Bjørås, Magnar
Boberg, Kirsten M.
Alseth, Ingrun
author_sort Forsbring, Monika
collection PubMed
description The human hMYH and NEIL1 genes encode DNA glycosylases involved in repair of oxidative base damage and mutations in these genes are associated with certain cancers. Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease characterized by inflammatory destruction of the biliary tree, is often complicated by the development of cholangiocarcinoma (CCA). Here, we aimed to investigate the influence of genetic variations in the hMYH and NEIL1 genes on risk of CCA in PSC patients. The hMYH and NEIL1 gene loci in addition to the DNA repair genes hOGG1, NTHL1 and NUDT1 were analyzed in 66 PSC patients (37 with CCA and 29 without cancer) by complete genomic sequencing of exons and adjacent intronic regions. Several single-nucleotide polymorphisms and mutations were identified and severe impairment of protein function was observed for three non-synonymous variants. The NEIL1 G83D mutant was dysfunctional for the major oxidation products 7,8-dihydro-8-oxoguanine (8oxoG), thymine glycol and dihydrothymine in duplex DNA, and the ability to perform δ-elimination at abasic sites was significantly reduced. The hMYH R260Q mutant had severe defect in adenine DNA glycosylase activity, whereas hMYH H434D could excise adenines from A:8oxoG pairs but not from A:G mispairs. We found no overall associations between the 18 identified variants and susceptibility to CCA in PSC patients; however, the impaired variants may be of significance for carcinogenesis in general. Our findings demonstrate the importance of complete resequencing of selected candidate genes in order to identify rare genetic variants and their possible contribution to individual susceptibility to cancer development.
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spelling pubmed-27042872009-07-02 Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma Forsbring, Monika Vik, Erik S. Dalhus, Bjørn Karlsen, Tom H. Bergquist, Annika Schrumpf, Erik Bjørås, Magnar Boberg, Kirsten M. Alseth, Ingrun Carcinogenesis Cancer Biology The human hMYH and NEIL1 genes encode DNA glycosylases involved in repair of oxidative base damage and mutations in these genes are associated with certain cancers. Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease characterized by inflammatory destruction of the biliary tree, is often complicated by the development of cholangiocarcinoma (CCA). Here, we aimed to investigate the influence of genetic variations in the hMYH and NEIL1 genes on risk of CCA in PSC patients. The hMYH and NEIL1 gene loci in addition to the DNA repair genes hOGG1, NTHL1 and NUDT1 were analyzed in 66 PSC patients (37 with CCA and 29 without cancer) by complete genomic sequencing of exons and adjacent intronic regions. Several single-nucleotide polymorphisms and mutations were identified and severe impairment of protein function was observed for three non-synonymous variants. The NEIL1 G83D mutant was dysfunctional for the major oxidation products 7,8-dihydro-8-oxoguanine (8oxoG), thymine glycol and dihydrothymine in duplex DNA, and the ability to perform δ-elimination at abasic sites was significantly reduced. The hMYH R260Q mutant had severe defect in adenine DNA glycosylase activity, whereas hMYH H434D could excise adenines from A:8oxoG pairs but not from A:G mispairs. We found no overall associations between the 18 identified variants and susceptibility to CCA in PSC patients; however, the impaired variants may be of significance for carcinogenesis in general. Our findings demonstrate the importance of complete resequencing of selected candidate genes in order to identify rare genetic variants and their possible contribution to individual susceptibility to cancer development. Oxford University Press 2009-07 2009-05-14 /pmc/articles/PMC2704287/ /pubmed/19443904 http://dx.doi.org/10.1093/carcin/bgp118 Text en © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
spellingShingle Cancer Biology
Forsbring, Monika
Vik, Erik S.
Dalhus, Bjørn
Karlsen, Tom H.
Bergquist, Annika
Schrumpf, Erik
Bjørås, Magnar
Boberg, Kirsten M.
Alseth, Ingrun
Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma
title Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma
title_full Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma
title_fullStr Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma
title_full_unstemmed Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma
title_short Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma
title_sort catalytically impaired hmyh and neil1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704287/
https://www.ncbi.nlm.nih.gov/pubmed/19443904
http://dx.doi.org/10.1093/carcin/bgp118
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