TY - JOUR
T1 - Transcriptome analysis reveals cyclobutane pyrimidine dimers as a major source of UV-induced DNA breaks
AU - Garinis, George A.
AU - Mitchell, James R.
AU - Moorhouse, Michael J.
AU - Hanada, Katsuhiro
AU - De Waard, Harm
AU - Vandeputte, Dimitri
AU - Jans, Judith
AU - Brand, Karl
AU - Smid, Marcel
AU - Van Der Spek, Peter J.
AU - Hoeijmakers, Jan H.J.
AU - Kanaar, Roland
AU - Van Der Horst, Gijsbertus T.J.
PY - 2005/11/16
Y1 - 2005/11/16
N2 - 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.
AB - 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.
KW - DNA damage
KW - Functional genomics
KW - Photolyase
KW - UV irradiation
UR - http://www.scopus.com/inward/record.url?scp=27844470581&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7600849
DO - 10.1038/sj.emboj.7600849
M3 - Article
C2 - 16252008
AN - SCOPUS:27844470581
SN - 0261-4189
VL - 24
SP - 3952
EP - 3962
JO - EMBO Journal
JF - EMBO Journal
IS - 22
ER -