Differential role of transcription-coupled repair in UVB-induced G2 arrest and apoptosis in mouse epidermis.
Nucleotide excision repair (NER), apoptosis, and cell-cycle regulation are major defense mechanisms against the carcinogenic effects of UVB light. NER eliminates UVB-induced DNA photolesions via two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). Defects in NER result in the human disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS), displaying severe UV sensitivity and in the case of XP, cancer proneness. We investigated the impact of deficiencies in NER subpathways on apoptosis, hyperplasia, and cell cycle progression in the epidermis of UVB-exposed CS group B (Csb(-/-)) mice (no TCR), XP group C (Xpc(-/-)) mice (no GGR), and XP group A (Xpa(-/-)) mice (no TCR and no GGR). On UVB treatment (250 J/m(2)), Xpa(-/-) and Csb(-/-) mice revealed an extensive apoptotic response in the skin, a blockage of cell cycle progression of epidermal cells, and strong hyperplasia. Interestingly, the absence of this apoptotic response in the skin of wild-type and Xpc(-/-) mice coincided with the ability of epidermal cells to enter the S phase. However, only epidermal cells of Xpc(-/-) mice subsequently became arrested in the G(2) phase. Our data demonstrate that TCR (and/or restoration of UVB-inhibited transcription) enables damaged cells to progress through S phase and prevents the induction of apoptosis and hyperplasia. G(2) arrest is manifest only under conditions of proficient TCR in combination with deficient GGR, indicating that epidermal cells become arrested in the G(2) phase as a result of persisting damage in their genome.
van Oosten
M
M
Department of Radiation Genetics and Chemical Mutagenesis MGC, Leiden University Medical Center, 2333 AL Leiden, The Netherlands.
Rebel
H
H
Friedberg
E C
EC
van Steeg
H
H
van der Horst
G T
GT
van Kranen
H J
HJ
Westerman
A
A
van Zeeland
A A
AA
Mullenders
L H
LH
de Gruijl
F R
FR
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D004260:DNA Repair / Q000235:genetics*; D000078404:Epidermal Cells; D004817:Epidermis / Q000528:radiation effects*; D016195:G2 Phase / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D016196:S Phase; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
D011948:Receptors, Antigen, T-Cell