Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand the heterogeneity in genetic predisposition to skin cancer in different nucleotide excision repair-deficient human syndromes, we studied repair of cyclobutane pyrimidine dimers (CPDs) and of pyrimidine(6-4)pyrimidone (6-4PP) photoproducts in cells from trichothiodystrophy (TTD) patients. TTD is not associated with increased incidence of skin cancer, although 50% of the patients are photosensitive and carry a defect in the nucleotide excision repair pathway, similar to Xeroderma pigmentosum patients. However, in striking contrast to TTD, Xeroderma pigmentosum is highly prone to cancer. To address this apparent paradox, two types of studies were conducted: (a) reactivation of UV-irradiated plasmids harboring actively transcribed reporter genes, with or without photolyase treatment before transfection of SV40-transformed fibroblasts; and (b) the kinetics of removal of UV-induced CPDs and 6-4PPs in genomic DNA by immunoblot analysis using lesion-specific mAbs in SV40-transformed and untransformed fibroblasts representative of all genetic TTD complementation groups. Results showed that all cell lines from photosensitive TTD patients efficiently express Cat or luciferase genes in transfected plasmids carrying non-CPD lesions, including 6-4PP, and display wild-type or near-wild-type (50-70% in 3 cell lines) 6-4PP repair in the overall genome after immunoblot analysis. However, CPD lesions (the repair of which is defective in the overall genome) also block the expression of the reporter gene in transfected plasmids. Two cell lines from nonphotosensitive TTD patients showed wild-type levels of repair for both photoproducts in overall genome. A model on the lesion-specific repair in the context of the molecular defect in TTD is proposed. The implication of the defective CPD repair and efficient 6-4PP repair subpathways in cancer prevention in TTD patients is discussed.
 ...
PMID:Different removal of ultraviolet photoproducts in genetically related xeroderma pigmentosum and trichothiodystrophy diseases. 767 Dec 43

We have used the replicating shuttle vector pR2 to determine the role of ultraviolet C (UVC)-induced cyclobutane pyrimidine dimers (CPDs) and nondimer photoproducts in mutagenesis in human trichothiodystrophy (TTD) cells and in their repair-proficient counterparts obtained after complementation with the wild-type XPD/ERCC2 repair gene (TTD + ERCC2 cells). Before transfection in human cells, the UVC-irradiated vector DNA was treated with Anacystis nidulans photolyase [photoreactivation (PR) procedure] that selectively removed CPDs, leaving nondimer photoproducts intact. The mutant frequency of the UV-irradiated pR2 plasmid treated by PR was similar after replication in TTD or in TTD + ERCC2 cells. This result indicates that TTD cells were able to repair nondimer photoproducts as efficiently as TTD cells complemented with the wild-type repair gene and that in TTD cells, CPDs were the major photoproducts generating an increased mutant frequency after UVC irradiation. Sequence analysis of > 300 mutant plasmids indicated that PR of the DNA increased the relative level of tandem mutations and decreased the relative level of multiple mutations in TTD cells. In both cell lines, we observed that CPDs mostly led to GC-AT transitions; whereas only nondimer photoproducts were responsible for the induction of GC-TA transversions in TTD and TTD + ERCC2 cells.
 ...
PMID:Cyclobutane pyrimidine dimers are the main mutagenic DNA photoproducts in DNA repair-deficient trichothiodystrophy cells. 942 65

One of the major critical factors for cancer proneness is the cell response to DNA damage. In this work, we used human DNA repair deficient cell lines to investigate the responses to ultraviolet irradiation that lead to apoptosis, and the influence of maintaining the cells resting in confluent state. UV-induced apoptosis is prevented in photolyase-proficient HeLa cells when cyclobutane pyrimidine dimers (CPDs) are removed by photorepair. At the same time, we show recovery of RNA synthesis, thus indicating that blockage of RNA transcription may trigger apoptosis in human cells. On the other hand, confluent primary XPC and trichothiodystrophy (TTD)/XPD cell lines, related to xeroderma pigmentosum and trichothiodystrophy repair syndromes, had a reduced and delayed apoptosis when compared to non-confluent cells. In contrast, XPA cells were similarly sensitive in both the confluent and non-confluent growing state. The effect of cellular confluence on UV-mediated apoptosis in CSB cells, related to Cockayne's syndrome, was unclear. Thus, these results indicate that the induction of apoptosis by UV light may also be affected by DNA replication. In addition, they argue for the use of confluent primary cells in studies of induction of apoptosis by UV, a condition close to skin cells in vivo.
 ...
PMID:Effect of cell confluence on ultraviolet light apoptotic responses in DNA repair deficient cells. 1464 17