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The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage

The potential for genetic change arising from specific single types of DNA lesion has been thoroughly explored, but much less is known about the mutagenic effects of DNA lesions present in clustered damage sites. Localized clustering of damage is a hallmark of certain DNA-damaging agents, particular...

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Detalles Bibliográficos
Autores principales: Shikazono, Naoya, Pearson, Colin, O'Neill, Peter, Thacker, John
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557791/
https://www.ncbi.nlm.nih.gov/pubmed/16893955
http://dx.doi.org/10.1093/nar/gkl503
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author Shikazono, Naoya
Pearson, Colin
O'Neill, Peter
Thacker, John
author_facet Shikazono, Naoya
Pearson, Colin
O'Neill, Peter
Thacker, John
author_sort Shikazono, Naoya
collection PubMed
description The potential for genetic change arising from specific single types of DNA lesion has been thoroughly explored, but much less is known about the mutagenic effects of DNA lesions present in clustered damage sites. Localized clustering of damage is a hallmark of certain DNA-damaging agents, particularly ionizing radiation. We have investigated the potential of a non-mutagenic DNA base lesion, 5,6-dihydrothymine (DHT), to influence the mutagenicity of 8-oxo-7,8-dihydroguanine (8-oxoG) when the two lesions are closely opposed. Using a bacterial plasmid-based assay we present the first report of a significantly higher mutation frequency for the clustered DHT and 8-oxoG lesions than for single 8-oxoG in wild-type and in glycosylase-deficient strains. We propose that endonuclease III has an important role in the initial stages of processing DHT/8-oxoG clusters, removing DHT to give an intermediate with an abasic site or single-strand break opposing 8-oxoG. We suggest that this mutagenic intermediate is common to several different combinations of base lesions forming clustered DNA damage sites. The MutY glycosylase, acting post-replication, is most important for reducing mutation formation. Recovered plasmids commonly gave rise to both wild-type and mutant progeny, suggesting that there is differential replication of the two DNA strands carrying specific forms of base damage.
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spelling pubmed-15577912006-09-07 The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage Shikazono, Naoya Pearson, Colin O'Neill, Peter Thacker, John Nucleic Acids Res Article The potential for genetic change arising from specific single types of DNA lesion has been thoroughly explored, but much less is known about the mutagenic effects of DNA lesions present in clustered damage sites. Localized clustering of damage is a hallmark of certain DNA-damaging agents, particularly ionizing radiation. We have investigated the potential of a non-mutagenic DNA base lesion, 5,6-dihydrothymine (DHT), to influence the mutagenicity of 8-oxo-7,8-dihydroguanine (8-oxoG) when the two lesions are closely opposed. Using a bacterial plasmid-based assay we present the first report of a significantly higher mutation frequency for the clustered DHT and 8-oxoG lesions than for single 8-oxoG in wild-type and in glycosylase-deficient strains. We propose that endonuclease III has an important role in the initial stages of processing DHT/8-oxoG clusters, removing DHT to give an intermediate with an abasic site or single-strand break opposing 8-oxoG. We suggest that this mutagenic intermediate is common to several different combinations of base lesions forming clustered DNA damage sites. The MutY glycosylase, acting post-replication, is most important for reducing mutation formation. Recovered plasmids commonly gave rise to both wild-type and mutant progeny, suggesting that there is differential replication of the two DNA strands carrying specific forms of base damage. Oxford University Press 2006 2006-08-07 /pmc/articles/PMC1557791/ /pubmed/16893955 http://dx.doi.org/10.1093/nar/gkl503 Text en © 2006 The Author(s)
spellingShingle Article
Shikazono, Naoya
Pearson, Colin
O'Neill, Peter
Thacker, John
The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage
title The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage
title_full The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage
title_fullStr The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage
title_full_unstemmed The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage
title_short The roles of specific glycosylases in determining the mutagenic consequences of clustered DNA base damage
title_sort roles of specific glycosylases in determining the mutagenic consequences of clustered dna base damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557791/
https://www.ncbi.nlm.nih.gov/pubmed/16893955
http://dx.doi.org/10.1093/nar/gkl503
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