Hedgehog (Hh) and transforming growth factor-B (TGF-B) family members are involved in numerous overlapping processes during embryonic development, hair cycle, and cancer. Herein, we show that TGF
Mutations in the CSA or CSB complementation genes cause the Cockayne syndrome, a severe genetic disorder that results in patients' death in early adulthood. CSA and CSB act in a transcription-coupled repair (TCR) pathway, but their functional relationship is not understood. We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome-and CSA-dependent manner. Moreover, we demonstrate the importance of CSB degradation for post-TCR recovery of transcription and for the Cockayne syndrome. Our results unravel for the first time the functional relationship between CSA and CSB. DNA damage represents a major threat for the maintenance of genomic integrity, and a variety of cellular pathways recognize and repair defects in DNA structure. Repair of UV-light-induced pyrimidine dimers or of adducts created by cisplatin is carried out by the nucleotide excision repair (NER) pathway. This pathway is impaired in several diseases such as Xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy (TTD), and the mild ultraviolet (UV)-light-sensitive syndrome (Bootsma et al. 1998).NER proceeds via two alternative pathways: The global genome repair (GGR) is involved in the repair of any sequence in the genome regardless of its transcriptional status; the transcription-coupled repair (TCR) is only involved in the repair of actively transcribed DNA strands. TCR occurs at a higher rate than GGR, but the reason for this difference is not fully understood. Most of the events of the two pathways are identical; in both cases, DNA unwinding is followed by excision of a 27-30-nucleotide oligonucleotide fragment containing the photoproduct of the damaged DNA strand and its replacement by de novo synthesis using the opposite, untouched, DNA strand as the template. Thus, the major difference between GGR and TCR occurs at the level of recognition of the DNA damage. In the GGR pathway, the damage is initially recognized via a direct interaction of NER proteins XPE and XPC-HR23B with damaged DNA. In contrast, in TCR, damages appear to be signaled via the stalling of RNA polymerase II (Pol II). The release of RNA polymerase involves two proteins, CSA and CSB, but their mode of action is unknown (Friedberg et al. 1995;Svejstrup 2002).CSA and CSB are TCR factors, the mutation of which causes the Cockayne syndrome. CSB is a member of the SWI2/SNF2 family of ATP-dependent chromatin remodeling factors and has the activities of SWI2/SNF2 proteins (Troelstra et al. 1992): DNA-dependent ATPase (but not classical helicase) (Selby and Sancar 1997b;Citterio et al. 1998), nucleosome remodeling, and interaction with core histones . In addition, CSB locally influences the DNA conformation, likely by wrapping the DNA around itself (Beerens et al. 2005), thereby modifying the interface between stalled RNA polymerase II and DNA. This modification promotes DNA repair or allows ...
Galectin-7 is a -galactoside binding protein specifically expressed in stratified epithelia and notably in epidermis, but barely detectable in epidermal tumors and absent from squamous carcinoma cell lines. Galectin-7 gene is an early transcriptional target of the tumor suppressor protein P53 [Polyak, K., Xia, Y., Zweier, J., Kinzler, K. & Vogelstein, B. (1997) Nature (London) 389, 300-305]. Because p53 transcriptional activity is increased by genotoxic stresses we have examined the possible effects of ultraviolet radiations (UVB) on galectin-7 expression in epidermal keratinocytes. The amounts of galectin-7 mRNA and protein are increased rapidly after UVB irradiation of epidermal keratinocytes. The increase of galectin-7 is parallel to P53 stabilization. UVB irradiation of skin reconstructed in vitro and of human skin ex vivo demonstrates that galectin-7 overexpression is associated with sunburn͞apoptotic keratinocytes. Transfection of a galectin-7 expression vector results in a significant increase in terminal deoxynucleotidyltransferase-mediated UTP end labeling-positive keratinocytes. The present findings demonstrate a keratinocyte-specific protein involved in the UVinduced apoptosis, an essential process in the maintenance of epidermal homeostasis.
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