Cargando…

Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity

DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide res...

Descripción completa

Detalles Bibliográficos
Autores principales: Mao, Peng, Brown, Alexander J., Malc, Ewa P., Mieczkowski, Piotr A., Smerdon, Michael J., Roberts, Steven A., Wyrick, John J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630031/
https://www.ncbi.nlm.nih.gov/pubmed/28912372
http://dx.doi.org/10.1101/gr.225771.117
_version_ 1783269161726640128
author Mao, Peng
Brown, Alexander J.
Malc, Ewa P.
Mieczkowski, Piotr A.
Smerdon, Michael J.
Roberts, Steven A.
Wyrick, John J.
author_facet Mao, Peng
Brown, Alexander J.
Malc, Ewa P.
Mieczkowski, Piotr A.
Smerdon, Michael J.
Roberts, Steven A.
Wyrick, John J.
author_sort Mao, Peng
collection PubMed
description DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad axis and is regulated by histone modifications. Our data also indicate that MMS-induced mutations at adenine nucleotides are significantly enriched on the nontranscribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers.
format Online
Article
Text
id pubmed-5630031
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-56300312018-04-01 Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity Mao, Peng Brown, Alexander J. Malc, Ewa P. Mieczkowski, Piotr A. Smerdon, Michael J. Roberts, Steven A. Wyrick, John J. Genome Res Research DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad axis and is regulated by histone modifications. Our data also indicate that MMS-induced mutations at adenine nucleotides are significantly enriched on the nontranscribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers. Cold Spring Harbor Laboratory Press 2017-10 /pmc/articles/PMC5630031/ /pubmed/28912372 http://dx.doi.org/10.1101/gr.225771.117 Text en © 2017 Mao et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Mao, Peng
Brown, Alexander J.
Malc, Ewa P.
Mieczkowski, Piotr A.
Smerdon, Michael J.
Roberts, Steven A.
Wyrick, John J.
Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
title Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
title_full Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
title_fullStr Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
title_full_unstemmed Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
title_short Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
title_sort genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630031/
https://www.ncbi.nlm.nih.gov/pubmed/28912372
http://dx.doi.org/10.1101/gr.225771.117
work_keys_str_mv AT maopeng genomewidemapsofalkylationdamagerepairandmutagenesisinyeastrevealmechanismsofmutationalheterogeneity
AT brownalexanderj genomewidemapsofalkylationdamagerepairandmutagenesisinyeastrevealmechanismsofmutationalheterogeneity
AT malcewap genomewidemapsofalkylationdamagerepairandmutagenesisinyeastrevealmechanismsofmutationalheterogeneity
AT mieczkowskipiotra genomewidemapsofalkylationdamagerepairandmutagenesisinyeastrevealmechanismsofmutationalheterogeneity
AT smerdonmichaelj genomewidemapsofalkylationdamagerepairandmutagenesisinyeastrevealmechanismsofmutationalheterogeneity
AT robertsstevena genomewidemapsofalkylationdamagerepairandmutagenesisinyeastrevealmechanismsofmutationalheterogeneity
AT wyrickjohnj genomewidemapsofalkylationdamagerepairandmutagenesisinyeastrevealmechanismsofmutationalheterogeneity