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A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site

The ubiquitous occurrence of DNA damages renders its repair machinery a crucial requirement for the genomic stability and the survival of living organisms. Deficiencies in DNA repair can lead to carcinogenesis, Alzheimer, or Diabetes II, where increased amounts of oxidized DNA bases have been found...

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Autores principales: Blank, Iris D., Sadeghian, Keyarash, Ochsenfeld, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445063/
https://www.ncbi.nlm.nih.gov/pubmed/26013033
http://dx.doi.org/10.1038/srep10369
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author Blank, Iris D.
Sadeghian, Keyarash
Ochsenfeld, Christian
author_facet Blank, Iris D.
Sadeghian, Keyarash
Ochsenfeld, Christian
author_sort Blank, Iris D.
collection PubMed
description The ubiquitous occurrence of DNA damages renders its repair machinery a crucial requirement for the genomic stability and the survival of living organisms. Deficiencies in DNA repair can lead to carcinogenesis, Alzheimer, or Diabetes II, where increased amounts of oxidized DNA bases have been found in patients. Despite the highest mutation frequency among oxidized DNA bases, the base-excision repair process of oxidized and ring-opened guanine, FapydG (2,6-diamino-4-hydroxy-5-formamidopyrimidine), remained unclear since it is difficult to study experimentally. We use newly-developed linear-scaling quantum-chemical methods (QM) allowing us to include up to 700 QM-atoms and achieving size convergence. Instead of the widely assumed base-protonated pathway we find a ribose-protonated repair mechanism which explains experimental observations and shows strong evidence for a base-independent repair process. Our results also imply that discrimination must occur during recognition, prior to the binding within the active site.
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spelling pubmed-44450632015-06-01 A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site Blank, Iris D. Sadeghian, Keyarash Ochsenfeld, Christian Sci Rep Article The ubiquitous occurrence of DNA damages renders its repair machinery a crucial requirement for the genomic stability and the survival of living organisms. Deficiencies in DNA repair can lead to carcinogenesis, Alzheimer, or Diabetes II, where increased amounts of oxidized DNA bases have been found in patients. Despite the highest mutation frequency among oxidized DNA bases, the base-excision repair process of oxidized and ring-opened guanine, FapydG (2,6-diamino-4-hydroxy-5-formamidopyrimidine), remained unclear since it is difficult to study experimentally. We use newly-developed linear-scaling quantum-chemical methods (QM) allowing us to include up to 700 QM-atoms and achieving size convergence. Instead of the widely assumed base-protonated pathway we find a ribose-protonated repair mechanism which explains experimental observations and shows strong evidence for a base-independent repair process. Our results also imply that discrimination must occur during recognition, prior to the binding within the active site. Nature Publishing Group 2015-05-27 /pmc/articles/PMC4445063/ /pubmed/26013033 http://dx.doi.org/10.1038/srep10369 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Blank, Iris D.
Sadeghian, Keyarash
Ochsenfeld, Christian
A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site
title A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site
title_full A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site
title_fullStr A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site
title_full_unstemmed A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site
title_short A Base-Independent Repair Mechanism for DNA Glycosylase—No Discrimination Within the Active Site
title_sort base-independent repair mechanism for dna glycosylase—no discrimination within the active site
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445063/
https://www.ncbi.nlm.nih.gov/pubmed/26013033
http://dx.doi.org/10.1038/srep10369
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