M. Van Oosten et al., Differential role of transcription-coupled repair in UVB-induced G(2) arrest and apoptosis in mouse epidermis, P NAS US, 97(21), 2000, pp. 11268-11273
Citations number
41
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Nucleotide excision repair (NER), apoptosis. and cell-cycle regulation are
major defense mechanisms against the carcinogenic: effects of UVB light. NE
R eliminates UVB-induced DNA photolesions via two subpathways: global genom
e repair (GGR) and transcription-coupled repair (TCR). Defects in NER resul
t in the human disorders xeroderma pigmentosum (XP) and Cockayne syndrome (
CS), displaying severe UV sensitivity and in the case of XP, cancer pronene
ss, We investigated the impact of deficiencies in NER subpathways on apopto
sis, hyperplasia, and cell cycle progression in the epidermis of UVB-expose
d 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 respons
e 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 ep
idermal cells to enter the S phase. However, only epidermal cells of Xpc(-/
-) mice subsequently became arrested in the G(2) phase. Our data demonstrat
e that TCR (and/or restoration of UVB-inhibited transcription) enables dama
ged cells to progress through S phase and prevents the induction of apoptos
is and hyperplasia, G(2) arrest is manifest only under conditions of profic
ient TCR in combination with deficient GGR, indicating that epidermal cells
become arrested in the G(2) phase as a result of persisting damage in thei
r genome.