Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1

Abstract Both a DNA lesion and an intermediate for antibody maturation, uracil is primarily processed by base excision repair (BER), either initiated by uracil-DNA glycosylase (UNG) or by single-strand selective monofunctional uracil DNA glycosylase (SMUG1). The relative in vivo contributions of eac...

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Autores principales:	Lene Alsøe, Antonio Sarno, Sergio Carracedo, Diana Domanska, Felix Dingler, Lisa Lirussi, Tanima SenGupta, Nuriye Basdag Tekin, Laure Jobert, Ludmil B. Alexandrov, Anastasia Galashevskaya, Cristina Rada, Geir Kjetil Sandve, Torbjørn Rognes, Hans E. Krokan, Hilde Nilsen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/200ff99a0e8a48df8df9562bc5e8eec8
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spelling	oai:doaj.org-article:200ff99a0e8a48df8df9562bc5e8eec82021-12-02T11:40:51ZUracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG110.1038/s41598-017-07314-52045-2322https://doaj.org/article/200ff99a0e8a48df8df9562bc5e8eec82017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07314-5https://doaj.org/toc/2045-2322Abstract Both a DNA lesion and an intermediate for antibody maturation, uracil is primarily processed by base excision repair (BER), either initiated by uracil-DNA glycosylase (UNG) or by single-strand selective monofunctional uracil DNA glycosylase (SMUG1). The relative in vivo contributions of each glycosylase remain elusive. To assess the impact of SMUG1 deficiency, we measured uracil and 5-hydroxymethyluracil, another SMUG1 substrate, in Smug1 −/− mice. We found that 5-hydroxymethyluracil accumulated in Smug1 −/− tissues and correlated with 5-hydroxymethylcytosine levels. The highest increase was found in brain, which contained about 26-fold higher genomic 5-hydroxymethyluracil levels than the wild type. Smug1 −/− mice did not accumulate uracil in their genome and Ung −/− mice showed slightly elevated uracil levels. Contrastingly, Ung −/− Smug1 −/− mice showed a synergistic increase in uracil levels with up to 25-fold higher uracil levels than wild type. Whole genome sequencing of UNG/SMUG1-deficient tumours revealed that combined UNG and SMUG1 deficiency leads to the accumulation of mutations, primarily C to T transitions within CpG sequences. This unexpected sequence bias suggests that CpG dinucleotides are intrinsically more mutation prone. In conclusion, we showed that SMUG1 efficiently prevent genomic uracil accumulation, even in the presence of UNG, and identified mutational signatures associated with combined UNG and SMUG1 deficiency.Lene AlsøeAntonio SarnoSergio CarracedoDiana DomanskaFelix DinglerLisa LirussiTanima SenGuptaNuriye Basdag TekinLaure JobertLudmil B. AlexandrovAnastasia GalashevskayaCristina RadaGeir Kjetil SandveTorbjørn RognesHans E. KrokanHilde NilsenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lene Alsøe Antonio Sarno Sergio Carracedo Diana Domanska Felix Dingler Lisa Lirussi Tanima SenGupta Nuriye Basdag Tekin Laure Jobert Ludmil B. Alexandrov Anastasia Galashevskaya Cristina Rada Geir Kjetil Sandve Torbjørn Rognes Hans E. Krokan Hilde Nilsen Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1
description	Abstract Both a DNA lesion and an intermediate for antibody maturation, uracil is primarily processed by base excision repair (BER), either initiated by uracil-DNA glycosylase (UNG) or by single-strand selective monofunctional uracil DNA glycosylase (SMUG1). The relative in vivo contributions of each glycosylase remain elusive. To assess the impact of SMUG1 deficiency, we measured uracil and 5-hydroxymethyluracil, another SMUG1 substrate, in Smug1 −/− mice. We found that 5-hydroxymethyluracil accumulated in Smug1 −/− tissues and correlated with 5-hydroxymethylcytosine levels. The highest increase was found in brain, which contained about 26-fold higher genomic 5-hydroxymethyluracil levels than the wild type. Smug1 −/− mice did not accumulate uracil in their genome and Ung −/− mice showed slightly elevated uracil levels. Contrastingly, Ung −/− Smug1 −/− mice showed a synergistic increase in uracil levels with up to 25-fold higher uracil levels than wild type. Whole genome sequencing of UNG/SMUG1-deficient tumours revealed that combined UNG and SMUG1 deficiency leads to the accumulation of mutations, primarily C to T transitions within CpG sequences. This unexpected sequence bias suggests that CpG dinucleotides are intrinsically more mutation prone. In conclusion, we showed that SMUG1 efficiently prevent genomic uracil accumulation, even in the presence of UNG, and identified mutational signatures associated with combined UNG and SMUG1 deficiency.
format	article
author	Lene Alsøe Antonio Sarno Sergio Carracedo Diana Domanska Felix Dingler Lisa Lirussi Tanima SenGupta Nuriye Basdag Tekin Laure Jobert Ludmil B. Alexandrov Anastasia Galashevskaya Cristina Rada Geir Kjetil Sandve Torbjørn Rognes Hans E. Krokan Hilde Nilsen
author_facet	Lene Alsøe Antonio Sarno Sergio Carracedo Diana Domanska Felix Dingler Lisa Lirussi Tanima SenGupta Nuriye Basdag Tekin Laure Jobert Ludmil B. Alexandrov Anastasia Galashevskaya Cristina Rada Geir Kjetil Sandve Torbjørn Rognes Hans E. Krokan Hilde Nilsen
author_sort	Lene Alsøe
title	Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1
title_short	Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1
title_full	Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1
title_fullStr	Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1
title_full_unstemmed	Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1
title_sort	uracil accumulation and mutagenesis dominated by cytosine deamination in cpg dinucleotides in mice lacking ung and smug1
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/200ff99a0e8a48df8df9562bc5e8eec8
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Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1

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