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Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence

8-Oxoguanine (8-oxoG) is a major product of oxidative DNA damage, which induces replication errors and interferes with transcription. By varying the position of single 8-oxoG in a functional gene and manipulating the nucleotide sequence surrounding the lesion, we found that the degree of transcripti...

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Autores principales: Allgayer, Julia, Kitsera, Nataliya, von der Lippen, Carina, Epe, Bernd, Khobta, Andriy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794583/
https://www.ncbi.nlm.nih.gov/pubmed/23863843
http://dx.doi.org/10.1093/nar/gkt620
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author Allgayer, Julia
Kitsera, Nataliya
von der Lippen, Carina
Epe, Bernd
Khobta, Andriy
author_facet Allgayer, Julia
Kitsera, Nataliya
von der Lippen, Carina
Epe, Bernd
Khobta, Andriy
author_sort Allgayer, Julia
collection PubMed
description 8-Oxoguanine (8-oxoG) is a major product of oxidative DNA damage, which induces replication errors and interferes with transcription. By varying the position of single 8-oxoG in a functional gene and manipulating the nucleotide sequence surrounding the lesion, we found that the degree of transcriptional inhibition is independent of the distance from the transcription start or the localization within the transcribed or the non-transcribed DNA strand. However, it is strongly dependent on the sequence context and also proportional to cellular expression of 8-oxoguanine DNA glycosylase (OGG1)—demonstrating that transcriptional arrest does not take place at unrepaired 8-oxoG and proving a causal connection between 8-oxoG excision and the inhibition of transcription. We identified the 5′-CAGGGC[8-oxoG]GACTG-3′ motif as having only minimal transcription-inhibitory potential in cells, based on which we predicted that 8-oxoG excision is particularly inefficient in this sequence context. This anticipation was fully confirmed by direct biochemical assays. Furthermore, in DNA containing a bistranded Cp[8-oxoG]/Cp[8-oxoG] clustered lesion, the excision rates differed between the two strands at least by a factor of 9, clearly demonstrating that the excision preference is defined by the DNA strand asymmetry rather than the overall geometry of the double helix or local duplex stability.
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spelling pubmed-37945832013-10-21 Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence Allgayer, Julia Kitsera, Nataliya von der Lippen, Carina Epe, Bernd Khobta, Andriy Nucleic Acids Res Genome Integrity, Repair and Replication 8-Oxoguanine (8-oxoG) is a major product of oxidative DNA damage, which induces replication errors and interferes with transcription. By varying the position of single 8-oxoG in a functional gene and manipulating the nucleotide sequence surrounding the lesion, we found that the degree of transcriptional inhibition is independent of the distance from the transcription start or the localization within the transcribed or the non-transcribed DNA strand. However, it is strongly dependent on the sequence context and also proportional to cellular expression of 8-oxoguanine DNA glycosylase (OGG1)—demonstrating that transcriptional arrest does not take place at unrepaired 8-oxoG and proving a causal connection between 8-oxoG excision and the inhibition of transcription. We identified the 5′-CAGGGC[8-oxoG]GACTG-3′ motif as having only minimal transcription-inhibitory potential in cells, based on which we predicted that 8-oxoG excision is particularly inefficient in this sequence context. This anticipation was fully confirmed by direct biochemical assays. Furthermore, in DNA containing a bistranded Cp[8-oxoG]/Cp[8-oxoG] clustered lesion, the excision rates differed between the two strands at least by a factor of 9, clearly demonstrating that the excision preference is defined by the DNA strand asymmetry rather than the overall geometry of the double helix or local duplex stability. Oxford University Press 2013-10 2013-07-17 /pmc/articles/PMC3794583/ /pubmed/23863843 http://dx.doi.org/10.1093/nar/gkt620 Text en © The Author(s) 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genome Integrity, Repair and Replication
Allgayer, Julia
Kitsera, Nataliya
von der Lippen, Carina
Epe, Bernd
Khobta, Andriy
Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence
title Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence
title_full Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence
title_fullStr Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence
title_full_unstemmed Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence
title_short Modulation of base excision repair of 8-oxoguanine by the nucleotide sequence
title_sort modulation of base excision repair of 8-oxoguanine by the nucleotide sequence
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794583/
https://www.ncbi.nlm.nih.gov/pubmed/23863843
http://dx.doi.org/10.1093/nar/gkt620
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