Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic compounds are human carcinogens. The ingested inorganic arsenic is metabolized to methylated derivatives, which are considered to be more toxic than the inorganic species. Interactions of trivalent arsenicals with thiol groups of proteins are believed to be important for arsenic carcinogenesis, but inorganic arsenite appears to bind to thiol groups more strongly than the methylated As (III) species. Inhibition of the nucleotide excision repair pathway of DNA repair (NER) is likely to be of primary importance in arsenic carcinogenesis. Previously, we demonstrated that methylated As (III) compounds are more efficient than arsenite in releasing zinc from ZnXPAzf, the zinc finger of XPA, a crucial member of the NER complex [Schwerdtle, T., Walter, I., and Hartwig, A. (2003) Arsenite and its biomethylated metabolites interfere with the formation and repair of stable BPDE-induced DNA adducts in human cells and impair XPAzf and Fpg. DNA Repair (Amsterdam) 2, 1449-1463]. In this work, we used ESI-MS to compare aerobic reactivities of arsenite and monomethylarsonous acid (MMA (III)) toward ZnXPAzf on the molecular level. We demonstrated that equimolar MMA (III) released Zn (II) from ZnXPAzf easily, forming mono- and diarsenical derivatives of XPAzf. This reaction was accompanied by oxidation of unprotected thiol groups of the monomethylarsinated peptide to intramolecular disulfides. The estimated affinity of MMA (III) to XPAzf is 30-fold higher than that established previously for arsenite binding to the thiol groups. No binding of arsenite to the thiol groups of XPAzf was observed under our experimental conditions, and a 10-fold excess of arsenite was required to partially oxidize ZnXPAzf. These results indicate a particular susceptibility of tetrathiolate zinc fingers to MMA (III), thereby providing a novel molecular pathway in arsenic carcinogenesis.
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PMID:Monomethylarsonous acid destroys a tetrathiolate zinc finger much more efficiently than inorganic arsenite: mechanistic considerations and consequences for DNA repair inhibition. 1822 Mar 66

In this population-based case-control study with 325 Caucasian renal cell carcinoma (RCC) patients and 335 controls matched to cases by age, gender and county of residence, we evaluated the associations between 13 potential functional polymorphisms in nine major nucleotide excision repair (NER) genes and RCC risk. In individual single nucleotide polymorphism analysis, after adjustment for multiple comparisons, a significantly decreased RCC risk was observed for the heterozygous genotype of XPD Asp312Asn [odds ratio (OR) = 0.62; 95% confidence interval (CI): 0.43-0.90] and for the heterozygous and homozygous variant genotypes combined in a dominant model (OR = 0.64; 95% CI: 0.46-0.89). The heterozygous AG genotype of XPA 5'untranslated region was at 1.78-fold increased risk (95% CI: 1.18-2.69) and the risk reached 2.43-fold (95% CI: 1.57-3.75) for the homozygous variant GG genotype; the risk was significant both in the dominant model and in the recessive model. In joint analysis, compared with individuals with fewer than five adverse alleles, individuals with five (OR = 1.17; 95% CI: 0.71-1.93), six (OR = 1.66; 95% CI: 1.03-2.67), seven or more (OR = 1.85; 95% CI: 1.16-2.95) exhibited a progressively increased risk of RCC (P for trend = 0.004). Further, there were significant interactions between NER pathway genes and sex, hypertension and obesity (all P for interaction <0.05). Our results strongly support that common sequence variants of the NER pathway genes predispose susceptible individuals to increased risk of RCC and that the association may be modified by gender, history of hypertension and obesity. These results need to be replicated in larger studies.
Carcinogenesis 2008 Nov
PMID:Case-control analysis of nucleotide excision repair pathway and the risk of renal cell carcinoma. 1871 Nov 49

We have reported that xeroderma pigmentosum group A (Xpa) gene-knockout mice [Xpa (-/-) mice] are deficient in nucleotide excision repair (NER) and highly sensitive to UV-induced skin carcinogenesis. Although xeroderma pigmentosum group A patients show growth retardation, immature sexual development, and neurological abnormalities as well as a high incidence of UV-induced skin tumors, Xpa (-/-) mice were physiologically and behaviorally normal. In the present study, we kept Xpa (-/-) mice for 2 years under specific pathogen-free (SPF) conditions and found that the testis diminished in an age-dependent manner, and degenerating seminiferous tubules and no spermatozoa were detected in the 24-month-old Xpa (-/-) mice. In addition, a higher incidence of spontaneous tumorigenesis was observed in the 24-month-old Xpa (-/-) mice compared to Xpa (+/+) controls. Xpa (-/-) mice provide a useful model for investigating the aging and internal tumor formation in XPA patients.
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PMID:Impaired spermatogenesis and elevated spontaneous tumorigenesis in xeroderma pigmentosum group A gene (Xpa)-deficient mice. 1879 90

Diets high in red meat have been consistently associated with colorectal cancer (CRC) risk and may result in exposure to carcinogens that cause DNA damage [i.e polycyclic aromatic hydrocarbons, heterocyclic amines (HCAs) and N-nitroso compounds]. Using a family-based study, we investigated whether polymorphisms in the nucleotide excision repair (NER) (ERCC1 3' untranslated region (UTR) G/T, XPD Asp312Asn and Lys751Gln, XPC intron 11 C/A, XPA 5' UTR C/T, XPF Arg415Gln and XPG Asp1104His) and mismatch repair (MLH1 Ile219Val and MSH2 Gly322Asp) pathways modified the association with red meat and poultry intake. We tested for gene-environment interactions using case-only analyses (n = 577) and compared the results using case-unaffected sibling comparisons (n = 307 sibships). Increased risk of CRC was observed for intake of more than or equal to three servings per week of red meat [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.3-2.5)] or high-temperature cooked red meat (OR = 1.6, 95% CI = 1.1-2.2). Intake of red meat heavily brown on the outside or inside increased CRC risk only among subjects who carried the XPD codon 751 Lys/Lys genotype (case-only interaction P = 0.006 and P = 0.001, respectively, for doneness outside or inside) or the XPD codon 312 Asp/Asp genotype (case-only interaction P = 0.090 and P < 0.001, respectively). These interactions were stronger for rectal cancer cases (heterogeneity test P = 0.002 for XPD Asp312Asn and P = 0.03 for XPD Lys751Gln) and remained statistically significant after accounting for multiple testing. Case-unaffected sibling analyses were generally supportive of the case-only results. These findings highlight the possible contribution of diets high in red meat to the formation of lesions that elicit the NER pathway, such as carcinogen-induced bulky adducts.
Carcinogenesis 2009 Mar
PMID:Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk. 1902 93

To investigate the mechanisms responsible for inter-organ differences in susceptibility to 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK)-induced carcinogenesis, the objectives were to compare DNA repair activities of extracts from mouse lung and liver towards NNK-induced pyridyloxobutyl (POB) damage to plasmid DNA, and to determine if and the mechanism by which in vivo NNK treatment of mice alters DNA repair. Repair activity of POB adducts was three times greater in mouse liver than in mouse lung (P<0.05). Repair activities of lung extracts from mice 4 or 24 h post-NNK treatment were 30-45% those of control (P<0.05). Conversely, POB adduct repair was 2-3 times higher in liver extracts from NNK treated mice than in controls (4 h, 24 h, P<0.05). NNK treatment also decreased incision of POB adducts by 92% (4 h, P<0.05) in lung and increased incision by 169% (24 h, P<0.05) in liver. NNK decreased immunoreactive levels of the incision protein RPA in lung (P<0.05) 4 h post-treatment but increased immunoreactive lung RPA and XPB after 24 h (P<0.05). In liver, levels of immunoreactive proteins, XPA, XPB and ERCC1 were increased after NNK treatment (24 h, P<0.05). Binding of XPA and XPB from liver extracts to POB adducts increased following NNK treatment, while binding of XPA and XPB from lung decreased (4 h, 24 h). These results suggest that lower incision activity of nucleotide excision repair and NNK-mediated alterations in levels and activities of key incision proteins contribute to the relative susceptibility of mouse lung to NNK-induced carcinogenesis.
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PMID:In vivo treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces organ-specific alterations in in vitro repair of DNA pyridyloxobutylation. 1915

Ionizing radiation (IR) imposes risks to human health and the environment. IR at low doses and low dose rates has the potency to initiate carcinogenesis. Genotoxic environmental agents such as IR trigger a cascade of signal transduction pathways for cellular protection. In this study, using cDNA microarray technique, we monitored the gene expression profiles in lymphocytes derived from radiation-exposed individuals (radiation workers). Physical dosimetry records on these patients indicated that the absorbed dose ranged from 0.696 to 39.088 mSv. Gene expression analysis revealed statistically significant transcriptional changes in a total of 78 genes (21 up-regulated and 57 down-regulated) involved in several biological processes such as ubiquitin cycle (UHRF2 and PIAS1), DNA repair (LIG3, XPA, ERCC5, RAD52, DCLRE1C), cell cycle regulation/proliferation (RHOA, CABLES2, TGFB2, IL16), and stress response (GSTP1, PPP2R5A, DUSP22). Some of the genes that showed altered expression profiles in this study can be used as biomarkers for monitoring the chronic low level exposure in humans. Additionally, alterations in gene expression patterns observed in chronically exposed radiation workers reinforces the need for defining the effective radiation dose that causes immediate genetic damage as well as the long-term effects on genomic instability, including cancer.
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PMID:Gene expression profiles in radiation workers occupationally exposed to ionizing radiation. 1921 81

In this case-control study with 387 White esophageal patients and 462 White controls matched to cases by age and sex, we evaluated the associations between 13 potential functional polymorphisms in eight major nucleotide excision repair (NER) genes and esophageal cancer risk. In individual single nucleotide polymorphism analysis, after adjustment for multiple comparisons, the heterozygous GT genotype of the ERCC1 3' untranslated region (UTR) was associated with an increased risk, whereas the homozygous variant genotype TT was associated with 60% reduction in risk with an odds ratio (OR) of 0.40 (95% confidence interval [CI] = 0.19-0.86). The heterozygous AG genotype of XPA 5' UTR was at 2.11-fold increased risk (95% CI = 1.33-3.35) and the risk reached 3.10-fold (95% CI = 1.94-4.95) for the homozygous variant GG genotype. These associations were also significant when restricted the analyses in patients with esophageal adenocarcinoma. Further, the CT genotype of the RAD23B Ala249Val was associated with increased esophageal cancer risk (OR = 1.44; 95% CI = 1.05-1.97), whereas the poly-AT-/+ genotype of the XPC intron 9 conferred a decreased risk (OR = 0.71, 95% CI = 0.51-0.97). In joint analysis, individuals carrying 1 (OR = 2.64, 95% CI = 1.57-4.52) and > or = 2 (OR = 2.74, 95% CI = 1.58-4.75) unfavorable genotypes exhibited significantly increased risk for esophageal cancer risk with significant dose-response trend (P for trend = 0.006). The pathway-based risk was more evident in ever smokers, overweight/obese individuals, men and ever drinkers. Our results support the hypothesis that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of esophageal cancer. These findings warrant further replications in different populations.
Carcinogenesis 2009 May
PMID:Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway. 1927

UVB-induced lesions in mammalian cellular DNA can, through the process of mutagenesis, lead to carcinogenesis. However, eukaryotic cells have evolved complex mechanisms of genomic surveillance and DNA damage repair to counteract the effects of UVB radiation. We show that following UVB DNA damage, there is an overall inhibition of protein synthesis and translational reprogramming. This reprogramming allows selective synthesis of DDR proteins, such as ERCC1, ERCC5, DDB1, XPA, XPD, and OGG1 and relies on upstream ORFs in the 5' untranslated region of these mRNAs. Experiments with DNA-PKcs-deficient cell lines and a specific DNA-PKcs inhibitor demonstrate that both the general repression of mRNA translation and the preferential translation of specific mRNAs depend on DNA-PKcs activity, and therefore our data establish a link between a key DNA damage signaling component and protein synthesis.
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PMID:Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes. 1945 Dec 21

Water-soluble and particulate cadmium compounds are carcinogenic to humans. While direct interactions with DNA are unlikely to account for carcinogenicity, induction of oxidative DNA damage and interference with DNA repair processes might be more relevant underlying modes of action (recently summarized, for example, in Joseph , P. (2009) Tox. Appl. Pharmacol. 238 , 271 - 279). The present study aimed to compare genotoxic effects of particulate CdO and soluble CdCl(2) in cultured human cells (A549, VH10hTert). Both cadmium compounds increased the baseline level of oxidative DNA damage. Even more pronounced, both cadmium compounds inhibited the nucleotide excision repair (NER) of BPDE-induced bulky DNA adducts and UVC-induced photolesions in a dose-dependent manner at noncytotoxic concentrations. Thereby, the uptake of cadmium in the nuclei strongly correlated with the repair inhibition of bulky DNA adducts, indicating that independent of the cadmium compound applied Cd(2+) is the common species responsible for the observed repair inhibition. Regarding the underlying molecular mechanisms in human cells, CdCl(2) (as shown before by Meplan, C., Mann, K. and Hainaut, P. (1999) J. Biol. Chem. 274 , 31663 - 31670 ) and CdO altered the conformation of the zinc binding domain of the tumor suppressor protein p53. In further studies applying only CdCl(2), cadmium decreased the total nuclear protein level of XPC, which is believed to be the principle initiator of global genome NER. This led to diminished association of XPC to sites of local UVC damage, resulting in decreased recruitment of further NER proteins. Additionally, CdCl(2) strongly disturbed the disassembly of XPC and XPA. In summary, our data indicate a general nucleotide excision repair inhibition by cadmium compounds, which is most likely caused by a diminished assembly and disassembly of the NER machinery. These data reveal new insights into the mechanisms involved in cadmium carcinogenesis and provide further evidence that DNA repair inhibition may be one predominant mechanism in cadmium induced carcinogenicity.
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PMID:Genotoxicity of soluble and particulate cadmium compounds: impact on oxidative DNA damage and nucleotide excision repair. 2009 76

This study was conducted to identify genetic factors predisposing to TP53 mutations in patients with non-small cell lung cancer (NSCLC). A comprehensive panel of potentially functional single nucleotide polymorphisms (SNPs) in DNA repair genes was evaluated in relation to TP53 mutations. Thirty-seven SNPs in 28 DNA repair genes were genotyped by a sequenome mass spectrometry-based genotyping assay in 173 NSCLCs and the associations with TP53 mutations in the entire coding exons (exons 2-11), including splicing sites of the gene, were analyzed. Four SNPs (XPA rs1800975, OGG1 rs1052133, ADPRT rs1136410, and NBS1 rs1805794) were significantly associated with the prevalence of TP53 mutations in multivariate analysis for each SNP. When the 4 SNPs were combined, the prevalence of TP53 mutations was increased as the number of bad genotypes increased (P(trend)=0.001). Patients with 3 and 4 bad genotypes had a significantly higher frequency of TP53 mutations than those with 0-1 bad genotypes (adjusted odds ratio=5.18, 95% confidence interval=1.51-17.81, P=0.01 and adjusted odds ratio=18.26, 95% confidence interval=2.87-116.09, P=0.002, respectively). These findings suggest that the 4 SNPs may modulate the occurrence of TP53 mutations and contribute to lung carcinogenesis. However, larger studies are required to confirm our findings in other ethnic populations.
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PMID:Associations between polymorphisms in DNA repair genes and TP53 mutations in non-small cell lung cancer. 2112 11


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