Transcriptome analysis reveals cyclobutane pyrimidine dimers as a major source of UV-induced DNA breaks

• DOI: 10.1038/sj.emboj.7600849
• Publication Date: 2005-10-27T07:23:29Z
• Authors: George A Garinis; James R Mitchell; Michael J Moorhouse; Katsuhiro Hanada; Harm de Waard; Dimitri Vandeputte; Judith Jans; Karl Brand; Marcel Smid; Peter J van der Spek; Jan H J Hoeijmakers; Roland Kanaar; Gijsbertus T J va...
• Keywords: DNA Repair; Proteome; Chromosomal Proteins, Non-Histone; Mice, Transgenic; Histones; Mice; 03 medical and health sciences; EMC MGC-02-02-01; Animals; Humans; Cells, Cultured; 0303 health sciences; Gene Expression Profiling; Cell Cycle; Intracellular Signaling Peptides and Proteins; EMC MM-03-24-01; Fibroblasts; Phosphoproteins; 3. Good health; EMC MM-03-32-04; DNA-Binding Proteins; Gene Expression Regulation; Pyrimidine Dimers; EMC MGC-01-12-03; Rad51 Recombinase; Deoxyribodipyrimidine Photo-Lyase; DNA Damage

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.