Germline ablation of SMUG1 DNA glycosylase causes loss of 5-hydroxymethyluracil-and UNG-backup uracil-excision activities and increases cancer predisposition of Ung-/-Msh2-/- mice

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DOIResolve DOI: http://doi.org/10.1093/nar/gks259
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TypeArticle
Journal titleNucleic Acids Research
ISSN0305-1048
Volume40
Issue13
Pages60166025; # of pages: 10
Subject5 hydroxymethyluracil; DNA glycosyltransferase; protein SMUG1; protein UNG; unclassified drug; uracil; animal cell; animal tissue; article; cancer susceptibility; controlled study; deamination; embryo; enzyme activity; gene; gene inactivation; knockout mouse; male; mouse; MSH2 gene; nonhuman; priority journal; SMUG1 gene; ung gene; Animals; beta-Galactosidase; Cell Line; DNA Repair; Fibroblasts; Fluorouracil; Gene Targeting; Genetic Predisposition to Disease; Longevity; Mice; Mice, Inbred C57BL; Mice, Knockout; MutS Homolog 2 Protein; Neoplasms, Experimental; Pentoxyl; Thymidine; Uracil-DNA Glycosidase; Mammalia; Mus
AbstractDeamination of cytosine (C), 5-methylcytosine (mC) and 5- hydroxymethylcytosine (hmC) occurs spontaneously in mammalian DNA with several hundred deaminations occurring in each cell every day. The resulting potentially mutagenic mispairs of uracil (U), thymine (T) or 5-hydroxymethyluracil (hmU) with guanine (G) are substrates for repair by various DNA glycosylases. Here,weshowthat targetedinactivation of the mouse Smug1 DNA glycosylase gene is sufficient to ablate nearly all hmU-DNA excision activity as judged by assay of tissue extracts from knockout mice as well as by the resistance of their embryo fibroblasts to 5-hydroxymethyldeoxyuridine toxicity. Inactivation of Smug1 when combined with inactivation of the Ung uracil-DNA glycosylase gene leads to a loss of nearly all detectable uracil excision activity. Thus, SMUG1 is the dominant glycosylase responsible for hmU-excision in mice as well as the major UNG-backup for U-excision. Both Smug1-knockout and Smug1/Ung-double knockout mice breed normally and remain apparently healthy beyond 1 year of age. However, combined deficiency in SMUG1 and UNG exacerbates the cancer predisposition of Msh2-/- mice suggesting that when both base excision and mismatch repair pathways are defective, the mutagenic effects of spontaneous cytosine deamination are sufficient to increase cancer incidence but do not preclude mouse development. © 2012 The Author(s).
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences (IBS-ISB)
Peer reviewedYes
NPARC number21269494
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Record identifierd041f676-5a4e-4352-b0d3-490588012617
Record created2013-12-12
Record modified2016-05-09
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