Garinis George A, Mitchell James R, Moorhouse Michael J, Hanada Katsuhiro, de Waard Harm, Vandeputte Dimitri, Jans Judith, Brand Karl, Smid Marcel, van der Spek Peter J, Hoeijmakers Jan H J, Kanaar Roland, van der Horst Gijsbertus T J
Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
EMBO J. 2005 Nov 16;24(22):3952-62. doi: 10.1038/sj.emboj.7600849. Epub 2005 Oct 27.
Photolyase transgenic mice have opened new avenues to improve our understanding of the cytotoxic effects of ultraviolet (UV) light on skin by providing a means to selectively remove either cyclobutane pyrimidine dimers (CPDs) or pyrimidine (6-4) pyrimidone photoproducts. Here, we have taken a genomics approach to delineate pathways through which CPDs might contribute to the harmful effects of UV exposure. We show that CPDs, rather than other DNA lesions or damaged macromolecules, comprise the principal mediator of the cellular transcriptional response to UV. The most prominent pathway induced by CPDs is that associated with DNA double-strand break (DSB) signalling and repair. Moreover, we show that CPDs provoke accumulation of gamma-H2AX, P53bp1 and Rad51 foci as well as an increase in the amount of DSBs, which coincides with accumulation of cells in S phase. Thus, conversion of unrepaired CPD lesions into DNA breaks during DNA replication may comprise one of the principal instigators of UV-mediated cytotoxicity.
光裂合酶转基因小鼠为我们深入了解紫外线（UV）对皮肤的细胞毒性作用开辟了新途径，它提供了一种选择性去除环丁烷嘧啶二聚体（CPD）或嘧啶（6-4）嘧啶酮光产物的方法。在此，我们采用基因组学方法来描绘CPD可能导致紫外线暴露有害影响的途径。我们发现，CPD而非其他DNA损伤或受损大分子，是细胞对紫外线转录反应的主要介导因子。CPD诱导的最显著途径是与DNA双链断裂（DSB）信号传导和修复相关的途径。此外，我们表明CPD会引发γ-H2AX、P53bp1和Rad51焦点的积累以及DSB数量的增加，这与S期细胞的积累相吻合。因此，在DNA复制过程中未修复的CPD损伤转化为DNA断裂可能是紫外线介导的细胞毒性的主要诱因之一。
