High incidence of epithelial cancers in mice deficient for DNA polymerase δ proofreading
High incidence of epithelial cancers in mice deficient for DNA polymerase δ proofreading
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DOI：
10.1073/pnas.232340999
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发表时间：
2002-11-26
影响因子：
11.1
通讯作者：
Preston, BD
中科院分区：
文献类型：
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作者：
Goldsby, RE;Hays, LE;Preston, BD
突变是癌症的一个标志。正常细胞通过聚合酶碱基选择性、3‘-->；5’外切核解核校对、错配纠正和DNA损伤修复的联合作用，最大限度地减少自发突变。为了确定在哺乳动物中有缺陷的校对的后果，我们创造了在DNA聚合酶Delta(PolDelta，由POLD1基因编码)的校对区域具有点突变(D400A)的小鼠。我们发现，该突变使PolDelta的3‘-->；5’外切酶失活，并以隐性方式导致突变子和癌症表型。到18个月大时，94%的纯合POLD1(D400A/D400A)小鼠患上癌症并死亡(中位生存期=10个月)。相比之下，在这段时间内，只有3-4%的POLD1(+/D400A)和POLD1(+/+)小鼠患上了癌症。在49只POLD1(D400A/D400A)小鼠的66个肿瘤中，40个是上皮来源(癌)，24个是间叶性的(淋巴瘤和肉瘤)，两个是复合性的(畸胎瘤)；这些动物中有三分之一的肿瘤发生在一个以上的组织中。皮肤鳞状细胞癌是最常见的肿瘤类型，发生在所有POLD1(D400A/D400A)小鼠中的60%和存活超过8个月的小鼠中的90%。这些数据表明，PolDelta校对抑制了自发的肿瘤发展，并强烈表明未修复的DNA聚合酶错误有助于癌症的发生。缺乏polDelta校对的小鼠提供了一个易于处理的模型来研究由突变子表型启动的上皮肿瘤发生的机制。
Mutations are a hallmark of cancer. Normal cells minimize spontaneous mutations through the combined actions of polymerase base selectivity, 3' --> 5' exonucleolytic proofreading, mismatch correction, and DNA damage repair. To determine the consequences of defective proofreading in mammals, we created mice with a point mutation (D400A) in the proofreading domain of DNA polymerase delta (poldelta, encoded by the Pold1 gene). We show that this mutation inactivates the 3' --> 5' exonuclease of poldelta and causes a mutator and cancer phenotype in a recessive manner. By 18 months of age, 94% of homozygous Pold1(D400A/D400A) mice developed cancer and died (median survival = 10 months). In contrast, only 3-4% of Pold1(+/D400A) and Pold1(+/+) mice developed cancer in this time frame. Of the 66 tumors arising in 49 Pold1(D400A/D400A) mice, 40 were epithelial in origin (carcinomas), 24 were mesenchymal (lymphomas and sarcomas), and two were composite (teratomas); one-third of these animals developed tumors in more than one tissue. Skin squamous cell carcinoma was the most common tumor type, occurring in 60% of all Pold1(D400A/D400A) mice and in 90% of those surviving beyond 8 months of age. These data show that poldelta proofreading suppresses spontaneous tumor development and strongly suggest that unrepaired DNA polymerase errors contribute to carcinogenesis. Mice deficient in poldelta proofreading provide a tractable model to study mechanisms of epithelial tumorigenesis initiated by a mutator phenotype.