Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymine-DNA glycosylase (TDG), a DNA repair enzyme specific for G/T mismatches, plays a role in the regulation of gene expression through its physical interaction with transcription factors. Here, we show that TDG functionally associates with members of the p53 tumor suppressor family and directly modulates their activity. Yeast two-hybrid analysis indicated a physical interaction between a region including the oligomerization domain (OD) of p73alpha (residues 345-380) or p53 (residues 319-360) and residues 123-346 of TDG, which localizes in the G/T glycosylase catalytic domain (residues 123-372). This interaction was also detected in vitro and in vivo by GST pull-down and immunoprecipitation assays, respectively. TDG over-expression promoted the p73- and p53-mediated transcriptional activation of the p21Waf1 promoter in a dose-dependent manner. Further, TDG enhanced the p53 or p73alpha-induced growth repression. These observations suggest that TDG modulates the biological function of p53 and other members of the p53 family as a transcriptional coactivator.
 ...
PMID:Thymine-DNA glycosylase interacts with and functions as a coactivator of p53 family proteins. 1895 77

Leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a surrogate marker of oxidant-induced DNA damage in patients undergoing maintenance hemodialysis (MHD). Glutathione S-transferase M1 (GST M1) is a member of the GST family of proteins, which protect cellular DNA against oxidative damage. This study tested the association of a common GST M1 gene polymorphism [GST M1(-)], known to produce a dysfunctional enzyme, with levels of 8-OHdG in peripheral blood leukocytes and all-cause mortality among MHD patients. Among 488 MHD patients and 372 gender-matched healthy subjects, the frequency of the GST M1(-) genotype was 63.1 and 60.2%, respectively. The GST M1(-) genotype was associated with significantly higher levels of leukocyte 8-OHdG compared with the GST M1(+) genotype, even after adjustment for potential confounders (P < 0.001). Moreover, GST M1(-) patients who also had a common polymorphism in the DNA repair enzyme 8-oxoguanine DNA glycosylase 1 or who underwent dialysis with a bioincompatible cellulose membrane had the highest median levels of leukocyte 8-OHdG. Multivariate Cox regression revealed that among MHD patients, GST M1(-) genotype approximately doubled the risk for all-cause mortality (hazard ratio 2.24; 95% confidence interval 1.30 to 4.51) during the mean follow-up of 34 mo. In conclusion, patients without GST M1 activity are more vulnerable to oxidative stress and are at greater risk for death compared with those who possess GST M1 activity.
 ...
PMID:GST M1 polymorphism associates with DNA oxidative damage and mortality among hemodialysis patients. 1905 70

Polynucleotide kinase/phosphatase (PNKP) is a bifunctional enzyme that can phosphorylate the 5'-OH termini and dephosphorylate the 3'-phosphate termini of DNA. It is a DNA repair enzyme involved in the processing of strand break termini, which permits subsequent repair proteins to replace missing nucleotides and rejoin broken strands. Little is known about DNA repair in Plasmodium falciparum, including the roles of PNKP in repairing parasite DNA. We identified a P. falciparum gene encoding a protein with 24% homology to human PNKP and thus suggestive of a putative PNKP. In this study, the PNKP gene of P. falciparum strain K1 (PfPNKP) was successfully cloned and expressed in E. coli as a GST-PfPNKP recombinant protein. MALDI-TOF/TOF analysis of the protein confirmed the identity of PfPNKP. Assays for enzymatic activity were carried out with a variety of single- and double-stranded substrates. Although 3'-phosphatase activity was detected, PfPNKP was observed to dephosphorylate single-stranded substrates or double-stranded substrates with a short 3'-single-stranded overhang, but not double-stranded substrates that mimicked single-strand breaks. We hypothesize that unlike human PNKP, PfPNKP may not be involved in single-strand break repair, since alternative terminal processing mechanisms can substitute for PfPNKP, and that PfPNKP DNA repair actions may be confined to overhanging termini of double-strand breaks.
 ...
PMID:Molecular characterization of Plasmodium falciparum putative polynucleotide kinase/phosphatase. 2182 Oct 66

The oil sands region of northern Alberta represents the world's largest reserves of bitumen, and the accelerated pace of industrial extraction activity has raised concern about the possible impacts on the Athabasca River and its tributaries. An ecotoxicogenomic study was undertaken on Oncorhynchus mykiss trout hepatocytes exposed to extracts of water samples near the oil sand development area, as well as to oil sands process-affected water (OSPW) extracts using the quantitative reverse transcriptase polymerase chain reaction technique. The expression of the following genes (mRNA) was monitored to track changes in xenobiotic biotransformation (CYP1A1, CYP3A4, glutathione S-transferase, multi-drug resistance transporter), estrogenicity (estrogen receptor and vitellogenin), oxidative stress (superoxide dismutase and metallothionein) and DNA repair activity (DNA ligase). The extent of DNA-aromatic hydrocarbon adducts was also determined in cells by immuno-staining. A comparative analysis of gene expression between the river/lake and OSPW samples revealed that CYP3A4, metallothioneins, DNA ligase and GST genes, were specifically expressed by OSPW. Cells exposed to OSPW, commercial naphthenic acids, and benzo(a)pyrene showed increased polyaromatic hydrocarbon DNA-adducts, as determined by cell immunofluorescence analysis. Other genes were induced by all types of water samples, although the induction potential was stronger in OSPW most of the time (e.g., VTG gene was expressed nearly 15-fold by surface waters from the lake and river samples but increased to a maximum of 31-fold in OSPW). A multivariate discriminant function analysis revealed that the lake and river water samples were well discriminated from the OSPW. The CYP3A4 gene was the most highly expressed gene in cells exposed to OSPW and responded less to the lake or river water in the Athabasca River area. This study identified a suite of gene targets that responded specifically to OSPW extracts, which could serve as toxicogenomic fingerprints of OSPW contamination.
 ...
PMID:Differential changes in gene expression in rainbow trout hepatocytes exposed to extracts of oil sands process-affected water and the Athabasca River. 2225 23