Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0268140 (XPF)
 549 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cells from patients suffering with xeroderma pigmentosum (XP) characterized by extreme sensitivity to UV light and a high incidence of skin tumors fall into seven complementation groups, XPA to XPG, and are lacking a functional helicase, endonuclease, or lesion-recognizing protein involved in the initial steps during nucleotide excision repair (NER); a number of proteins involved in DNA repair are termed XPA to XPG depending on which one is defective in a particular complementation group of XP and include: (i) proteins involved in the recognition of (6-4) photoproducts (XPE) and of a broad range of lesions such as pyrimidine dimers (XPA); (ii) proteins that are DNA helicases and integral parts of the general transcription factor TFIIH functioning in both transcription and repair (XPB, XPD); (iii) endonucleases that perform the two incisions, the XPG incising six nucleotides (nt) to the 3' side from a photodimer and the ERCC1-XPF protein complex incising 22 nt to the 5' side of the lesion; and (iv) single-strand DNA-binding proteins (XPC). The ERCC6 helicase is largely responsible for coupling transcription to repair whereas XPC seems to be responsible for the repair of the inactive parts of the genome as well as for the repair of the nontranscribed strand in active genes. p53 recognizes insertion/deletion mismatches as well as free ends of DNA produced by ionizing radiation to arrest the cell cycle. Most of the human DNA repair proteins have their counterparts in both budding and fission yeasts and some of them also in E. coli evoking an evolutionary conservation of DNA repair pathways. Accumulation of mutations within repair genes in single cells followed by their escape from the immune surveillance and in clonal expansion may greatly contribute to the appearance and development of human cancers.
 ...
PMID:Xeroderma pigmentosum and molecular cloning of DNA repair genes. 868 16

Polymorphisms in six genes involved in nucleotide excision repair of DNA were examined in a large population-based case-control study of melanoma. Genotyping was conducted for 2485 patients with a single primary melanoma (controls) and 1238 patients with second or higher order primary melanomas (cases). Patients were ascertained from nine geographic regions in Australia, Canada, Italy and the United States. Positive associations were observed for XPD 312 Asn/Asn versus Asp/Asp [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.2-1.9] and XPD 751 Gln/Gln versus Lys/Lys (OR = 1.4, 95% CI 1.1-1.7) genotypes and melanoma. The combined XPD Asn (A) 312 + Gln (C) 751 haplotype was significantly more frequent in cases (32%) compared with controls (29%) (P = 0.003) and risk of melanoma increased significantly with one and two copies of the haplotype (ORs 1.2, 95% CI 1.0-1.4, and 1.6, 95% CI 1.2-2.0, trend P = 0.002). No significant associations were observed for HR23B codon 249, XPG codon 1104, XPC codon 939, XPF codon 415, XPF nt 2063, ERCC6 codon 1213 or ERCC6 codon 1230. ORs for XPD and XPC genotypes were stronger for melanoma diagnosed at an early age, but tests for interaction were not statistically significant. The results provide further evidence for a role of XPD in the etiology of melanoma.
 ...
PMID:Polymorphisms in nucleotide excision repair genes and risk of multiple primary melanoma: the Genes Environment and Melanoma Study. 1625 77

Polymorphisms exist in several genes involved in nucleotide excision repair (NER), the principal pathway for removal of smoking-induced DNA damage. An epidemiologic study was conducted to determine whether these polymorphisms modify the association between smoking and breast cancer. DNA samples and exposure histories were analyzed as part of a large population-based case-control study of breast cancer in North Carolina. The study population included 2311 cases (894 African Americans, 1417 whites) and 2022 controls (788 African Americans, 1234 whites). Odds ratios (ORs) were calculated for breast cancer and smoking, and for breast cancer and nine non-synonymous coding polymorphisms in six NER genes (XPD codons 312 and 751, RAD23B codon 249, XPG codon 1104, XPC codon 939, XPF codons 415 and 662, and ERCC6 codons 1213 and 1230). Modification of ORs for smoking by single and combined NER genotypes was investigated. In this study population, smoking was more strongly associated with breast cancer in African American women compared with white women. Among African American women, the association of breast cancer and smoking was strongest among women with specific combinations of NER genotypes. Evidence for multiplicative interaction was found between combined NER genotypes and smoking dose (likelihood ratio test P = 0.06), duration (P = 0.09), time since cessation (P = 0.02), age at initiation (P = 0.04) and former smoking (P = 0.03). No interactions were observed in white women. Therefore, polymorphisms in NER genes may modify the relationship between breast cancer and smoking. These results are consistent with previous evidence of exposure-specific p53 mutations in breast tumors from current and former smokers, suggesting that smoking may play a role in breast cancer etiology.
 ...
PMID:Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case-control study. 1639 71

Prostate cancer is a common malignancy that disproportionately affects African-American men. Environmental factors and variation in genes responsible for chemical and dietary carcinogen metabolism and DNA damage repair may modulate risk. Fourteen single nucleotide polymorphisms in NAT2 and four NER genes (ERCC1, XPF/ERCC4, XPG/ERCC5 and CSB/ERCC6) were genotyped in a case-control study of 254 African-American prostate cancer cases and 301 healthy controls from Washington, DC. Smoking status, BMI, age and genetic ancestry were included as covariates in the association analyses. We found that individuals homozygous for the XPG/ERCC5 -72C/T promoter polymorphism had a significant reduction in risk, for prostate cancer (OR=0.12; 95% CI=0.03-0.48). A haplotype trend regression test also revealed a protective effect for the haplotype bearing the T allele (P=0.003). In silica analyses suggest a functional implication for the promoter variant since it deletes a GCF transcriptional factor-binding site responsible for the downregulation of transcription. The protective effect of the promoter SNP on risk for prostate cancer was independent of smoking. In contrast, none of the SNPs typed for NAT2, ERCC1, ERCC4 and ERCC6 showed significant association with risk. Additional tests for genotype interactions were not significant. We note that there may be other factors, such as dietary exposures, which may modulate prostate cancer risk in combination with genetic variation within the NAT2 and NER genes. Our results, in combination with previous observations of LOH for ERCC5 in prostate tumors, provide further evidence for a role of XPG/ERCC5 in the etiology of prostate cancer.
 ...
PMID:NAT2 and NER genetic variants and sporadic prostate cancer susceptibility in African Americans. 1802 84

Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case-control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (OR(GC) = 1.1, OR(CC) = 1.3; p-trend = 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/Gy(GG) = 1.0, 95% CI = <0, 6.0; EOR/Gy(GC/CC) = 5.9, 95% CI = 0.9, 14.4; p(het) = 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/Gy(AA) = 9.1, 95% CI = 2.1-21.3; EOR/Gy(AC/CC) = 0.6, 95% CI = <0, 4.6; p(het) = 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk.
 ...
PMID:Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists. 1876 34

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.
 ...
PMID:Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. 2362 89