Department of Toxicogenetics, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands.
Curr Biol. 2010 Jan 26;20(2):170-5. doi: 10.1016/j.cub.2009.11.061. Epub 2009 Dec 31.
Skin cancer is the most ubiquitous cancer type in the Caucasian population, and its incidence is increasing rapidly [1]. Transcribed proliferation-related genes in dermal stem cells are targets for the induction of ultraviolet light (UV)-induced mutations that drive carcinogenesis. We have recently found that transcription of a gene increases its mutability by UV in mammalian stem cells, suggesting a role of transcription in skin carcinogenesis [2]. Here we show that transcription-associated UV-induced nucleotide substitutions are caused by increased deamination of cytosines to uracil within photolesions at the transcribed strand, presumably at sites of stalled transcription complexes. Additionally, via an independent mechanism, transcription of UV-damaged DNA induces the generation of intragenic deletions. We demonstrate that transcription-coupled nucleotide excision repair (TC-NER) provides protection against both classes of transcription-associated mutagenesis. Combined, these results unveil the existence of two mutagenic pathways operating specifically at the transcribed DNA strand of active genes. Moreover, these results uncover a novel role for TC-NER in the suppression of UV-induced genome aberrations and provide a rationale for the efficient induction of apoptosis by stalled transcription complexes.
皮肤癌是白种人群体中最普遍的癌症类型，其发病率正在迅速上升[1]。真皮干细胞中与转录有关的基因是紫外线（UV）诱导突变的靶点，这些突变驱动致癌作用。我们最近发现，在哺乳动物干细胞中，基因的转录会增加其对 UV 的突变率，这表明转录在皮肤癌发生中起作用[2]。在这里，我们表明转录相关的 UV 诱导核苷酸取代是由转录链上光损伤中胞嘧啶脱氨为尿嘧啶引起的，推测是在停滞转录复合物的部位[2]。此外，通过独立的机制，UV 损伤 DNA 的转录诱导基因内缺失的产生。我们证明转录偶联核苷酸切除修复（TC-NER）可提供对两类转录相关诱变的保护[2]。综上所述，这些结果揭示了两种在活跃基因的转录 DNA 链上特异性起作用的诱变途径的存在[2]。此外，这些结果揭示了 TC-NER 在抑制 UV 诱导的基因组畸变中的新作用，并为停滞转录复合物有效诱导细胞凋亡提供了依据[2]。
