Eller M S, Maeda T, Magnoni C, Atwal D, Gilchrest B A
Boston University Medical School, Department of Dermatology, Boston, MA 02118-2394, USA.
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12627-32. doi: 10.1073/pnas.94.23.12627.
Thymidine dinucleotide (pTpT) stimulates melanogenesis in mammalian pigment cells and intact skin, mimicking the effects of UV irradiation and UV-mimetic DNA damage. Here it is shown that, in addition to tanning, pTpT induces a second photoprotective response, enhanced repair of UV-induced DNA damage. This enhanced repair results in a 2-fold increase in expression of a UV-damaged chloramphenicol acetyltransferase expression vector transfected into pTpT-treated skin fibroblasts and keratinocytes, compared with diluent-treated cells. Direct measurement of thymine dimers and (6-4) photoproducts by immunoassay demonstrates faster repair of both of these UV-induced photoproducts in pTpT-treated fibroblasts. This enhanced repair capacity also improves cell survival and colony-forming ability after irradiation. These effects of pTpT are accomplished, at least in part, by the up-regulation of a set of genes involved in DNA repair (ERCC3 and GADD45) and cell cycle inhibition (SDI1). At least two of these genes (GADD45 and SDI1) are known to be transcriptionally regulated by the p53 tumor suppressor protein. Here we show that pTpT activates p53, leading to nuclear accumulation of this protein, and also increases the specific binding of this transcription factor to its DNA consensus sequence.
胸腺嘧啶二核苷酸（pTpT）可刺激哺乳动物色素细胞和完整皮肤中的黑色素生成，模拟紫外线照射和紫外线模拟DNA损伤的作用。本文表明，除了晒黑外，pTpT还诱导第二种光保护反应，即增强紫外线诱导的DNA损伤修复。与用稀释剂处理的细胞相比，这种增强的修复导致转染到经pTpT处理的皮肤成纤维细胞和角质形成细胞中的紫外线损伤氯霉素乙酰转移酶表达载体的表达增加两倍。通过免疫测定直接测量胸腺嘧啶二聚体和（6-4）光产物表明，在经pTpT处理的成纤维细胞中，这两种紫外线诱导的光产物的修复速度更快。这种增强的修复能力还提高了照射后细胞的存活率和集落形成能力。pTpT的这些作用至少部分是通过上调一组参与DNA修复（ERCC3和GADD45）和细胞周期抑制（SDI1）的基因来实现的。已知这些基因中至少有两个（GADD45和SDI1）受p53肿瘤抑制蛋白的转录调控。本文表明，pTpT激活p53，导致该蛋白在细胞核中积累，并且还增加了该转录因子与其DNA共有序列的特异性结合。
