Transcriptome analysis reveals cyclobutane pyrimidine dimers as a major source of UV-induced DNA breaks.
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.
Garinis
George A
GA
Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Mitchell
James R
JR
Moorhouse
Michael J
MJ
Hanada
Katsuhiro
K
de Waard
Harm
H
Vandeputte
Dimitri
D
Jans
Judith
J
Brand
Karl
K
Smid
Marcel
M
van der Spek
Peter J
PJ
Hoeijmakers
Jan H J
JH
Kanaar
Roland
R
van der Horst
Gijsbertus T J
GT
D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004255:Deoxyribodipyrimidine Photo-Lyase / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D011740:Pyrimidine Dimers; D051135:Rad51 Recombinase / Q000378:metabolism; D014158:Transcription, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1; D014466:Ultraviolet Rays
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D020543:Proteome; D011740:Pyrimidine Dimers; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; C475961:gamma-H2AX protein, mouse; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D004255:Deoxyribodipyrimidine Photo-Lyase