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

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. Here, 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 ofmore » UNG, and identified mutational signatures associated with combined UNG and SMUG1 deficiency.« less
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [4] ;  [1] ;  [1] ;  [1] ;  [5] ; ORCiD logo [6] ;  [7] ; ORCiD logo [4] ;  [3] ; ORCiD logo [8] ;  [9] ; ORCiD logo [1]
  1. Univ. of Oslo (Norway). Dept. of Clinical Molecular Biology; Akershus Univ. Hospital, Lorenskog (Norway)
  2. Norwegian Univ. of Science and Technology, Trondheim (Norway); Liaison Committee for Education, Research and Innovation in Central Norway, Trondheim (Norway)
  3. Univ. of Oslo (Norway). Dept. of Informatics
  4. Medical Research Council (MRC), Cambridge (United Kingdom). Lab. of Molecular Biology (MRC-LMB)
  5. Univ. of Oslo (Norway). Dept. of Clinical Molecular Biology; Akershus Univ. Hospital, Lorenskog (Norway); LifeTechnologies AS, Oslo (Norway)
  6. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of New Mexico Comprehensive Cancer Center, Albuquerque, NM (United States)
  7. Norwegian Univ. of Science and Technology, Trondheim (Norway
  8. Univ. of Oslo (Norway). Dept. of Informatics; Oslo University Hospital, Oslo (Norway). Dept. of Microbiology
  9. Norwegian Univ. of Science and Technology, Trondheim (Norway)
Publication Date:
Report Number(s):
LA-UR-16-28917
Journal ID: ISSN 2045-2322
Grant/Contract Number:
AC52-06NA25396; 4501723–2013; 2014001; 609020
Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 7; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; Norwegian Research Council; Norwegian Cancer Society; European Union (EU)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science; Base excision repair; DNA
OSTI Identifier:
1392805

Alsøe, Lene, Sarno, Antonio, Carracedo, Sergio, Domanska, Diana, Dingler, Felix, Lirussi, Lisa, SenGupta, Tanima, Tekin, Nuriye Basdag, Jobert, Laure, Alexandrov, Ludmil B., Galashevskaya, Anastasia, Rada, Cristina, Sandve, Geir Kjetil, Rognes, Torbjørn, Krokan, Hans E., and Nilsen, Hilde. Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1. United States: N. p., Web. doi:10.1038/s41598-017-07314-5.
Alsøe, Lene, Sarno, Antonio, Carracedo, Sergio, Domanska, Diana, Dingler, Felix, Lirussi, Lisa, SenGupta, Tanima, Tekin, Nuriye Basdag, Jobert, Laure, Alexandrov, Ludmil B., Galashevskaya, Anastasia, Rada, Cristina, Sandve, Geir Kjetil, Rognes, Torbjørn, Krokan, Hans E., & Nilsen, Hilde. Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1. United States. doi:10.1038/s41598-017-07314-5.
Alsøe, Lene, Sarno, Antonio, Carracedo, Sergio, Domanska, Diana, Dingler, Felix, Lirussi, Lisa, SenGupta, Tanima, Tekin, Nuriye Basdag, Jobert, Laure, Alexandrov, Ludmil B., Galashevskaya, Anastasia, Rada, Cristina, Sandve, Geir Kjetil, Rognes, Torbjørn, Krokan, Hans E., and Nilsen, Hilde. 2017. "Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1". United States. doi:10.1038/s41598-017-07314-5. https://www.osti.gov/servlets/purl/1392805.
@article{osti_1392805,
title = {Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1},
author = {Alsøe, Lene and Sarno, Antonio and Carracedo, Sergio and Domanska, Diana and Dingler, Felix and Lirussi, Lisa and SenGupta, Tanima and Tekin, Nuriye Basdag and Jobert, Laure and Alexandrov, Ludmil B. and Galashevskaya, Anastasia and Rada, Cristina and Sandve, Geir Kjetil and Rognes, Torbjørn and Krokan, Hans E. and Nilsen, Hilde},
abstractNote = {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. Here, 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.},
doi = {10.1038/s41598-017-07314-5},
journal = {Scientific Reports},
number = 1,
volume = 7,
place = {United States},
year = {2017},
month = {8}
}