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

被引：77

作者：

Kemmerich, Kristin ^{[1
]}

Dingler, Felix A. ^{[1
]}

Rada, Cristina ^{[1
]}

Neuberger, Michael S. ^{[1
]}

机构：

[1] MRC, Mol Biol Lab, Cambridge CB2 0QH, England

来源：

NUCLEIC ACIDS RESEARCH | 2012年 / 40卷 / 13期

基金：

英国医学研究理事会;

关键词：

BASE EXCISION; 5-METHYLCYTOSINE-DNA GLYCOSYLASE; SOMATIC HYPERMUTATION; DEAMINATED CYTOSINE; MAMMALIAN-CELLS; DEFICIENT MICE; REPAIR ENZYME; GENOME-WIDE; DEMETHYLATION; MECHANISMS;

D O I：

10.1093/nar/gks259

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Deamination 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.

引用

页码：6016 / 6025

页数：10