Increased susceptibility to UV-induced skin carcinogenesis in polymerase η-deficient mice
Increased susceptibility to UV-induced skin carcinogenesis in polymerase η-deficient mice
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DOI：
10.1158/0008-5472.can-05-1862
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Kucherlapati, R
中科院分区：
文献类型：
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作者：
Lin, QC;Clark, AB;Kucherlapati, R
具有DNA聚合酶eta （pol eta）基因突变的着色性干皮变异体（XPV）患者对阳光过敏，并且对阳光诱发的皮肤癌的易感性大大增加。与Pot eta有效绕过紫外光诱导的环丁烷嘧啶二聚体的能力一致，缺乏Pot eta的XPV细胞复制紫外线损伤DNA的能力降低，并且对紫外光诱导的杀伤和诱变敏感。为了更好地了解这些和其他Pol eta功能，我们产生了Pot eta缺陷小鼠。pol - eta零突变纯合子的小鼠是存活的，可生育的，并且在生命的第一年不会表现出任何明显的自发缺陷。然而，来自这些突变小鼠的成纤维细胞对暴露在紫外线下的杀伤很敏感，所有缺乏Pot eta的小鼠在紫外线照射后都会产生皮肤肿瘤，而野生型对照小鼠则不会产生这种肿瘤。这些结果和小鼠Pol eta转译合成的生化研究表明，环丁烷嘧啶二聚体的Pot eta依赖旁路抑制紫外光诱导的小鼠皮肤癌。此外，在5个月的紫外线照射后，37.5%的pol eta杂合小鼠在5个月内也患上了皮肤癌，这表明pol eta突变杂合的人类患皮肤癌的风险也可能增加。
Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase eta (pol eta) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pot eta to efficiently bypass UV light-induced cyclobutane pyrimidine dimers, XPV cells lacking Pot eta have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light-induced killing and mutagenesis. To better understand these and other Pol eta functions, we generated Pot eta-deficient mice. Mice homozygous for a null mutation in pol eta are viable, fertile, and do not show any obvious spontaneous defects during the first year of life. However, fibroblasts derived from these mutant mice are sensitive to killing by exposure to UV light, and all Pot eta-deficient mice develop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did not develop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol eta indicate that Pot eta-dependent bypass of cyclobutane pyrimidine dimers suppresses UV light-induced skin cancer in mice. Moreover, 37.5% of pol eta heterozygous mice also developed skin cancer during 5 months after a 5-month exposure to UV light, suggesting that humans who are heterozygous for mutations in pol eta may also have an increased risk of skin cancer.