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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Main Authors:	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
Format:	Article
Language:	English
Published:	Nature Publishing Group 2017-08-01
Series:	Scientific Reports
Online Access:	https://doi.org/10.1038/s41598-017-07314-5

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spelling	doaj-200ff99a0e8a48df8df9562bc5e8eec82020-12-08T02:35:34ZengNature Publishing GroupScientific Reports2045-23222017-08-017111410.1038/s41598-017-07314-5Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1Lene Alsøe0Antonio Sarno1Sergio Carracedo2Diana Domanska3Felix Dingler4Lisa Lirussi5Tanima SenGupta6Nuriye Basdag Tekin7Laure Jobert8Ludmil B. Alexandrov9Anastasia Galashevskaya10Cristina Rada11Geir Kjetil Sandve12Torbjørn Rognes13Hans E. Krokan14Hilde Nilsen15Department of Clinical Molecular Biology, Ahus Campus, University of OsloDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and TechnologyDepartment of Clinical Molecular Biology, Ahus Campus, University of OsloDepartment of Informatics, University of OsloMRC Laboratory of Molecular BiologyDepartment of Clinical Molecular Biology, Ahus Campus, University of OsloDepartment of Clinical Molecular Biology, Ahus Campus, University of OsloDepartment of Clinical Molecular Biology, Ahus Campus, University of OsloDepartment of Clinical Molecular Biology, Ahus Campus, University of OsloTheoretical Biology and Biophysics (T-6), Los Alamos National LaboratoryDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and TechnologyMRC Laboratory of Molecular BiologyDepartment of Informatics, University of OsloDepartment of Informatics, University of OsloDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and TechnologyDepartment of Clinical Molecular Biology, Ahus Campus, University of OsloAbstract 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.https://doi.org/10.1038/s41598-017-07314-5
collection	DOAJ
language	English
format	Article
sources	DOAJ
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
spellingShingle	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 Scientific Reports
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 Publishing Group
series	Scientific Reports
issn	2045-2322
publishDate	2017-08-01
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.
url	https://doi.org/10.1038/s41598-017-07314-5
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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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