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

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. Van Der Horst

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

136 Citaten (Scopus)

Samenvatting

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 γ-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.

Originele taal-2Engels
Pagina's (van-tot)3952-3962
Aantal pagina's11
TijdschriftEMBO Journal
Volume24
Nummer van het tijdschrift22
DOI's
StatusGepubliceerd - 16 nov. 2005
Extern gepubliceerdJa

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