The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice
The error-prone DNA polymerase ι provides quantitative resistance to lung tumorigenesis and mutagenesis in mice
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DOI：
10.1038/onc.2013.331
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发表时间：
2014-07-03
期刊：
影响因子：
8
通讯作者：
Lee, G-H
中科院分区：
文献类型：
--
作者：
Iguchi, M.;Osanai, M.;Lee, G-H
与未受损的核苷酸T相反，DNA聚合酶i（Poli）优先结合G而不是A，违反沃森-克里克规则。虽然Poli的实际生物学作用仍然是个谜，但我们已经确定其编码基因为肺腺瘤抗性2（Par 2）的候选基因，Par 2是一种调节化学诱导的肺肿瘤易感性的小鼠数量性状基因座。值得注意的是，129 X1/SvJ小鼠所拥有的最具肿瘤敏感性的Par 2等位基因与Poli中的功能丧失突变相关。为了确定非功能性Poli是否负责129 X1/SvJ特异性Par 2表型，我们在携带肿瘤敏感性较低的Par 2等位基因的C57 BL/6 J小鼠中敲除Poli。C57 BL/6 J Poli的破坏赋予C57 BL/6 J Par 2位点129 X1/SvJ样敏感性，并增加了肺中的体内突变频率，提供了明确的证据，即Poli引起Par 2效应并抑制肿瘤发生和诱变，尽管其极端复制不忠实。
Opposite undamaged nucleotide T, DNA polymerase iota (Poli) preferentially incorporates G rather than A, violating the Watson-Crick rule. Although the actual biological role of Poli remains enigmatic, we have identified its coding gene as a candidate for pulmonary adenoma resistance 2 (Par2), a mouse quantitative trait locus modulating chemically induced lung tumor susceptibility. Notably, the most tumor-sensitive Par2 allele possessed by the 129X1/SvJ mouse is associated with a loss-of-function mutation in Poli. To determine whether the nonfunctional Poli is responsible for the 129X1/SvJ-specific Par2 phenotype, we knocked out Poli in a C57BL/6J mouse carrying a less tumor-sensitive Par2 allele. Disruption of the C57BL/6J Poli conferred 129X1/SvJ-like sensitivity on the C57BL/6J Par2 locus and increased the in vivo mutation frequency in the lung, providing definitive proof that Poli causes the Par2 effect and inhibits tumorigenesis and mutagenesis, despite its extreme replication infidelity.