Participation of mouse DNA polymerase ι in strand-biased mutagenic bypass of UV photoproducts and suppression of skin cancer
Participation of mouse DNA polymerase ι in strand-biased mutagenic bypass of UV photoproducts and suppression of skin cancer
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DOI：
10.1073/pnas.0605247103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Kunkel, Thomas A.
中科院分区：
文献类型：
--
作者：
Dumstorf, Chad A.;Clark, Alan B.;Kunkel, Thomas A.
DNA聚合酶iota（pol iota）是一种保守的Y家族酶，其涉及跨损伤DNA合成（TLS），但其细胞功能仍不确定。为了检验pol L在细胞中进行TLS的假设，我们比较了来自野生型小鼠与缺乏功能性pol eta、pol iota或两者的小鼠的原代成纤维细胞中的UV诱导的诱变。小鼠DNA聚合酶eta（pol eta）的缺乏增强了紫外线诱导的Hprt突变频率。这种增强的UV诱导的诱变和野生型细胞中的UV诱导的诱变在缺乏pol的细胞中强烈减弱，表明pol参与细胞中UV光产物的旁路。此外，在野生型细胞中观察到UV诱导的碱基取代之间的明显链偏差，该偏差在pol eta和pol eta缺陷小鼠细胞中减少，并且在两种酶缺陷的细胞中消除。这些数据表明，这些酶旁路UV光产物以不对称的方式。为了确定pol i ota状态是否影响癌症易感性，我们比较了野生型小鼠与缺乏功能性pol eta、pol i ota或两者的小鼠的UV诱导的皮肤癌易感性。虽然单独的pol i ota缺乏没有影响，但pol i ota缺乏小鼠中的UV诱导的皮肤肿瘤在pol i ota伴随缺乏的小鼠中提前4周发生。总的来说，这些数据揭示了Pot L在绕过UV光产物和延迟UV诱导的皮肤癌发病方面的功能。
DNA polymerase iota (pol iota) is a conserved Y family enzyme that is implicated in translesion DNA synthesis (TLS) but whose cellular functions remain uncertain. To test the hypothesis that pol L performs TLS in cells, we compared UV-induced mutagenesis in primary fibroblasts derived from wild-type mice to mice lacking functional pol eta, pol iota, or both. A deficiency in mouse DNA polymerase eta (pol eta) enhanced UV-induced Hprt mutant frequencies. This enhanced UV-induced mutagenesis and UV-induced mutagenesis in wild-type cells were strongly diminished in cells deficient in pol iota, indicating that pol t participates in the bypass of UV photoproducts in cells. Moreover, a clear strand bias among UV-induced base substitutions was observed in wild-type cells that was diminished in pol eta- and pol iota-deficient mouse cells and abolished in cells deficient in both enzymes. These data suggest that these enzymes bypass UV photoproducts in an asymmetric manner. To determine whether pol iota status affects cancer susceptibility, we compared the UV-induced skin cancer susceptibility of wild-type mice to mice lacking functional pol eta, pol iota, or both. Although pol iota deficiency alone had no effect, UV-induced skin tumors in pol eta-deficient mice developed 4 weeks earlier in mice concomitantly deficient in pol iota. Collectively, these data reveal functions for Pot L in bypassing UV photoproducts and in delaying the onset of UV-induced skin cancer.