N-nitrosodimethylamine (NDMA) is a DNA methylating agent that has been discovered to contaminate water, food and drugs. The alkyladenine glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we studied Aag-/- and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine, or 3MeA) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switched from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrated a suite of molecular, cellular and physiological analyses. We found that unrepaired 3MeA is somewhat toxic but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tips the balance between blocks and breaks, and thus dictates the disease consequences of DNA damage.

中文翻译：

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切除致突变复制的病变可抑制癌症，但可促进暴露于亚硝胺的小鼠的细胞毒性和致死性

N-亚硝基二甲胺（NDMA）是一种DNA甲基化剂，已发现其会污染水，食物和药物。烷基腺嘌呤糖基化酶（AAG）去除甲基化的碱基以启动碱基切除修复（BER）途径。为了了解基因与环境之间的相互作用如何影响疾病的易感性，我们研究了Aag-/-和Aag过表达的小鼠，它们分别具有增加水平的复制阻滞性损伤（3-甲基腺嘌呤或3MeA）或链断裂（BER中间体）。值得注意的是，仅通过改变AAG的水平，疾病的结局就从癌症变成了致死性。为了了解该观察的基础，我们整合了一套分子，细胞和生理学分析。我们发现未修复的3MeA具有一定毒性，但具有高度致突变性（促进癌症），而多余的断链则致突变性差且毒性很高（抑制癌症并促进致死性）。我们证明了单个DNA修复蛋白的水平提示了阻滞和断裂之间的平衡，从而决定了DNA损伤的疾病后果。