Enhanced DDB2 expression protects mice from carcinogenic effects of chronic UV-B irradiation
Enhanced DDB2 expression protects mice from carcinogenic effects of chronic UV-B irradiation
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DOI：
10.1158/0008-5472.can-05-2295
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Mullenders, LHF
中科院分区：
文献类型：
--
作者：
Alekseev, S;Kool, H;Mullenders, LHF
紫外线损伤DNA结合蛋白（UV-DDB）是紫外线诱导的环丁烷嘧啶二聚体（CPD）的全基因组修复（GGR）所必需的。与人类细胞不同，啮齿动物表皮细胞缺乏CPD的GGR，并以低水平表达UVDDB的亚基DDB 2。在这项研究中，我们产生了小鼠（K14-DDB 2）异位表达小鼠DDB 2在升高的水平。DDB 2的表达增强既延迟了鳞状细胞癌的发生，又减少了慢性UV-B光暴露无毛小鼠中每只小鼠的肿瘤数量。DDB 2的表达增强改善了皮肤成纤维细胞中CPD和嘧啶（6-4）嘧啶酮光产物（6-4PP）的修复。然而，K14-DDB 2小鼠中CPD的GGR没有达到人细胞的效率水平，这表明当DDB 2大量存在时，另一种修复蛋白可能成为限速蛋白。为了补充这些研究，我们产生了DDB 2基因被破坏的小鼠。发现DDB 2-/-和DDB 2 +/-小鼠对UV诱导的皮肤致癌作用过敏。在细胞水平上，我们检测到DDB 2-/-真皮成纤维细胞中6- 4PP的修复延迟。DDB 2的缺乏或增强表达均不影响表皮角质形成细胞或培养的真皮成纤维细胞中UV诱导的凋亡水平。我们的研究结果表明DDB 2在保护免受紫外线诱导的癌症中起着重要作用，并表明这种保护最有可能是通过加速光损伤的修复来介导的。
UV-damaged DNA-binding protein (UV-DDB) is essential for global genome repair (GGR) of UV-induced cyclobutane pyrimidine dimers (CPD). Unlike human cells, rodent epidermal cells are deficient in GGR of CPDs and express a subunit of UVDDB, DDB2, at a low level. In this study, we generated mice (K14-DDB2) ectopically expressing mouse DDB2 at elevated levels. Enhanced expression of DDB2 both delayed the onset of squamous cell carcinoma and decreased the number of tumors per mouse in chronically UV-B light-exposed hairless mice. Enhanced expression of DDB2 improved repair of both CPDs and pyrimidine(6-4)pyrimidone photoproducts (6-4PP) in dermal fibroblasts. However, GGR of CPDs in K14-DDB2 mice did not reach the level of efficiency of human cells, suggesting that another repair protein may become rate limiting when DDB2 is abundantly present. To complement these studies, we generated mice in which the DDB2 gene was disrupted. DDB2-/- and DDB2+/- mice were found to be hypersensitive to UV-induced skin carcinogenesis. On the cellular level, we detected a delay in the repair of 6-4PPs in DDB2-/- dermal fibroblasts. Neither the absence nor the enhanced expression of DDB2 affected the levels of UV-induced apoptosis in epidermal keratinocytes or cultured dermal fibroblasts. Our results show an important role for DDB2 in the protection against UV-induced cancer and indicate that this protection is most likely mediated by accelerating the repair of photolesions.