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)

Sib patients with xeroderma pigmentosum (XP), XP90TO (42 years old, male) and XP92TO (40 years old, female, were assigned to group F by the complementation analysis in hybridized heterodikaryons. The XP90TO and XP92TO fibroblasts exhibited the typical XPF characteristics of a threefold higher sensitivity to the lethal effect of 254 nm UV and a reduced level of 12% unscheduled DNA synthesis (UDS) compared with normal cells. Clinically, both patients manifested moderate to severe acute sun sensitivity by age 8, pigmented freckles by age 10 and skin malignancies at higher ages (6 basaliomas at 42 years in XP90TO; 1 basalioma at 41 years in XP92TO). Despite the still currently sun-sensitive state, the patients showed normal minimal erythema dose (MED) at monochromatic wavelengths of 290, 300 and 305 nm but abnormally delayed peaking of erythema reaction at 48 h after exposure. After irradiation with more than 3 MED, XP92TO showed a long persistence of induced erythema for at least 7 days. A review of the 16 reported XPF patients indicated mild skin manifestations, no neurological abnormalities, and more delayed skin carcinogenesis at a lower frequency than that in XPA patients. In addition, we have collected clinical information from Japanese XP patients in rare complementation groups D and E and reviewed their clinical and photobiological characteristics.
 ...
PMID:Late onset of skin cancers in 2 xeroderma pigmentosum group F siblings and a review of 30 Japanese xeroderma pigmentosum patients in groups D, E and F. 266 29

XP-F cDNA was cloned into a mammalian expression vector plasmid, and introduced into group F xeroderma pigmentosum (XP-F) cells. Several cell clones possessing transfected XPF cDNA were randomly isolated, and DNA repair characteristics of a clone, XP-FR2, were extensively analyzed. The XP-FR2 cells expressed high level of XPF protein as well as ERCC1 protein, although their parental XP-F cells expressed extremely low level of both proteins. The XP-FR2 cells showed UV resistance comparable to normal human cells, and had normal levels of UV-induced unscheduled DNA synthesis and normal capability to remove cyclobutane pyrimidine dimers and (6-4) photoproducts. Frequencies and types of UV-induced mutations examined by shuttle vector plasmids in XP-FR2 cells were similar to those in normal human cells. These results demonstrate that excision repair defect in XP-F cells is fully corrected by over-expression of XPF cDNA alone, although only partial correction of the cells by XPF cDNA has been reported before.
Carcinogenesis 1998 Jan
PMID:Complete restoration of normal DNA repair characteristics in group F xeroderma pigmentosum cells by over-expression of transfected XPF cDNA. 947 93

The genetic disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS) exhibit deficiencies in the repair of UV-induced DNA damage. CS fibroblasts retain proficient nucleotide excision repair (NER) of inactive (or bulk) DNA, but are deficient in the transcription-coupled repair (TCR) of active genes. In contrast, XP complementation group C (XP-C) fibroblasts retain proficient TCR, but are deficient in bulk DNA repair. The remaining NER-deficient XP groups exhibit deficiencies in both repair pathways. Ad5HCMVsp1lacZ is a recombinant adenovirus vector that is unable to replicate in human fibroblasts, but can efficiently infect and express the beta-galactosidase reporter gene in these cells. We have examined the host cell reactivation (HCR) of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ in non-irradiated and UV-irradiated normal, XP-B, XP-C, XP-D, XP-F, XP-G, CS-A and CS-B fibroblasts. HCR of beta-galactosidase activity for UV-irradiated Ad5HCMVsp1lacZ was reduced in non-irradiated cells from each of the repair-deficient groups examined (including XP-C) relative to that in non-irradiated normal cells. Prior irradiation of cells with low UV fluences resulted in an enhancement of HCR for normal and XP-C strains, but not for the remaining XP and CS strains. HCR of the UV-damaged reporter gene in UV-irradiated XP and CS strains was similar to measurements of TCR reported previously for these cells. These results suggest that UV treatment results in an induced repair of UV-damaged DNA in the transcribed strand of an active gene in XP-C and normal cells through an enhancement of TCR or a mechanism which involves the TCR pathway.
Carcinogenesis 1999 Jan
PMID:UV-enhanced reactivation of a UV-damaged reporter gene suggests transcription-coupled repair is UV-inducible in human cells. 993 45

The hypersensitivity of Fanconi anemia, complementation group A, (FA-A) cells to agents which produce DNA interstrand cross-links correlates with a defect in their ability to repair this type of damage. In order to more clearly elucidate this repair defect, chromatin-associated protein extracts from FA-A cells were examined for ability to endonucleolytically produce incisions in DNA at sites of interstrand cross-links. A defined 140 bp DNA substrate was constructed with a single site-specific monoadduct or interstrand cross-link produced by 4,5',8-trimethylpsoralen (TMP) plus long wavelength (UVA) light. Our results show that FA-A cells are defective in ability to produce dual incisions in DNA at sites of interstrand cross-links. Specifically, there is defective incision on the 3'- and 5'-sides of both the furan and pyrone sides of the cross-link. This defect is corrected in FA-A cells transduced with a retroviral vector expressing FANCA cDNA. At the site of a TMP monoadduct, FA-A cells can introduce incisions on both the 3'- and 5'-sides of the furan side monoadduct, but are defective in ability to produce these incisions on the pyrone side monoadduct. These studies also indicate that XPF is involved in production of the 5' incision by the normal extracts on these substrates. These results correlate with our previous work, which showed that FA-A cells are mainly defective in ability to repair psoralen interstrand cross-links with a lesser defect in ability to repair psoralen monoadducts. This defect in endonucleolytic incision at sites of TMP interstrand cross-links could be related to reduced levels of non-erythroid alpha spectrin (alphaSpIISigma*) in the extracts from FA-A cells. alphaSpIISigma* could act as a scaffold to align proteins involved in cross-link repair and enhance their interactions; a deficiency in alphaSpIISigma* could thus lead to reduced efficiency of repair and the decreased levels of incisions we observe at sites of interstrand cross-links in FA-A cells.
Carcinogenesis 2000 Apr
PMID:Fanconi anemia, complementation group A, cells are defective in ability to produce incisions at sites of psoralen interstrand cross-links. 1075 11

DNA-protein crosslinks (DPC) involving all major histones are the dominant form of DNA damage in formaldehyde-exposed cells. In order to understand the repair mechanisms for these lesions we conducted detailed analysis of the stability of formaldehyde-induced DPC in vitro and in human cells. DNA-histone linkages were found to be hydrolytically unstable, with t(1/2) = 18.3 h at 37 degrees C. When histones were allowed to remain bound to DNA after crosslink breakage, the half-life of DPC increased to 26.3 h. This suggests that approximately 30% of spontaneously broken DPC could be re-established under physiological conditions. The half-lives of DPC in three human cell lines (HF/SV fibroblasts, kidney Ad293 and lung A549 cells) were similar and averaged 12.5 h (range 11.6-13.0 h). After adjustment for spontaneous loss, an active repair process was calculated to eliminate DPC from these cells with an average t(1/2) = 23.3 h. Removal of DPC from peripheral human lymphocytes was slower (t(1/2) = 18.1 h), due to inefficient active repair (t(1/2) = 66.6 h). This indicates that the major portion of DPC is lost from lymphocytes through spontaneous hydrolysis rather than being actively repaired. Depletion of intracellular glutathione from A549 cells had no significant effect on the initial levels of DPC, the rate of their repair or cell survival. Nucleotide excision repair does not appear to be involved in the removal of DPC, since the kinetics of DPC elimination in XP-A and XP-F fibroblasts were very similar to normal cells. Incubation of normal or XP-A cells with lactacystin, a specific inhibitor of proteosomes, caused inhibition of DPC repair, suggesting that the active removal of DPC in cells may involve proteolytic degradation of crosslinked proteins. XP-F cells showed somewhat higher sensitivity to formaldehyde, possibly signaling participation of XPF protein in the removal of residual peptide-DNA adducts.
Carcinogenesis 2000 Aug
PMID:Loss of DNA-protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome function. 1091 Sep 61

Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of lung cancer. The frequencies of several amino acid substitutions in XRCC1 (Arg194Trp, Arg280His and Arg399Gln), XRCC3 (Thr241Met), XPD (Ile199Met, His201Tyr, Asp312Asn and Lys751Gln) and XPF (Pro379Ser) genes were studied in 96 non-small-cell lung cancer (NSCLC) cases and in 96 healthy controls matched for age, gender and cigarette smoking. The XPD codon 312 Asp/Asp genotype was found to have almost twice the risk of lung cancer when the Asp/Asn + Asn/Asn combined genotype served as reference [odds ratio (OR) 1.86, 95% confidence interval (CI), 1.02-3.40]. In light cigarette smokers (less than the median of 34.5 pack-years), the XPD codon 312 Asp/Asp genotype was more frequent among cases than in controls and was associated with an increased risk of NSCLC. Compared with the Asn/Asn carriers, the OR in light smokers with the Asp/Asn genotype was 1.70 (CI0.35 0.43-6.74) and the OR in those with the Asp/Asp genotype was 5.32 (CI0.35-21.02) (P trend = 0.01). The 312 Asp/Asp genotype was not associated with lung cancer risk in never-smokers or heavy smokers (>34.5 pack-years). The XPD-312Asp and -751Lys polymorphisms were in linkage disequilibrium in the group studied; this finding was further supported by pedigree analysis of four families from Utah. The XPD 312Asp amino acid is evolutionarily conserved and is located in the seven-motif helicase domain of the RecQ family of DNA helicases. Our results indicate that these polymorphisms in the XPD gene should be investigated further for the possible attenuation of DNA repair and apoptotic functions and that additional molecular epidemiological studies are warranted to extend these findings.
Carcinogenesis 2001 Apr
PMID:Genetic polymorphisms in DNA repair genes and risk of lung cancer. 1128 94

The deficiencies of nucleotide excision repair (NER) factors are involved in rare genetic diseases such as xeroderma pigmentosum (XP) with increased risk of developing cancer on sun-exposed areas of the skin. However, the abnormality of NER factors in human sporadic carcinoma remains unclear. Loss of heterozygosity (LOH) analysis, using the microdissected tissues, for the XPA, XPB, XPC, XPD, XPE, XPF, XPG and the transcription-coupled repair factor, Cockayne syndrome B (CSB) revealed that NER factors were abnormal in 30.0% (3/10 cases) of oral squamous cell carcinomas. Furthermore, 10.0% of oral carcinomas exhibited LOH for NER factors without LOH for tumor suppressor genes such as p53, FHIT, APC, BRCA1, BRCA2 and DCC. These observations raise the possibility that alterations of NER factors may be involved in carcinogenesis in human oral squamous cell carcinoma.
 ...
PMID:Loss of heterozygosity of nucleotide excision repair factors in sporadic oral squamous cell carcinoma using microdissected tissue. 1149 30

Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.
 ...
PMID:Polymorphisms in DNA repair genes and associations with cancer risk. 1249 39

Arsenic is well established as a human carcinogen, but its precise mechanism of action remains unknown. Arsenic does not directly damage DNA, but may act as a carcinogen through inhibition of DNA repair mechanisms, leading indirectly to increased mutations from other DNA damaging agents. The molecular mechanism underlying arsenic inhibition of nucleotide excision repair after UV irradiation (Hartwig et al., Carcinogenesis 1997;18:399-405) is unknown, but could be due to decreased expression of critical genes involved in nucleotide excision repair of damaged DNA. This hypothesis was tested by analyzing expression of repair genes and arsenic exposure in a subset of 16 individuals enrolled in a population based case-control study investigating arsenic exposure and cancer risk in New Hampshire. Toenail arsenic levels were inversely correlated with expression of critical members of the nucleotide excision repair complex, ERCC1 (r(2) = 0.82, p < 0.0001), XPF (r(2) = 0.56, p < 0.002), and XPB (r(2) = 0.75, p < 0.0001). The internal dose marker, toenail arsenic level, was more strongly associated with changes in expression of these genes than drinking water arsenic concentration. Our findings, based on human exposure to arsenic in a US population, show an association between biomarkers of arsenic exposure and expression of DNA repair genes. Although our findings need verification in a larger study group, they are consistent with the hypothesis that inhibition of DNA repair capacity is a potential mechanism for the co-carcinogenic activity of arsenic.
 ...
PMID:Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water. 1256 48

DNA repair has an essential role in protecting the genome from damage by endogenous and environmental agents. Polymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely documented. For colorectal cancer, the loss of mismatch repair gene activity is a key genetic determinant. Nucleotide excision repair (NER), recombination repair (RR) and base excision repair (BER) pathways have critical roles in protection against other cancers, and we wished to investigate their role in colorectal cancer. We have compared the frequency of polymorphisms in the NER genes, XPD, XPF, XPG, ERCC1; in the BER gene, XRCC1; and in the RR gene, XRCC3; in colorectal cancer patients and in a control group. No significant associations were found for any of the NER gene polymorphisms or for the XRCC1 polymorphism. The C allele (position 18067) of the XRCC3 gene was weakly but significantly associated with colorectal cancer (odds ratio 1.52, 95% confidence interval 1.04-2.22, P=0.03). For all patients who were heterozygous for any of the repair genes studied, tumour tissue was investigated for loss of heterozygosity (LOH). Only one example of LOH was found for all the genes examined. From the association and LOH data, we conclude that these genes do not have an important role in protection against colorectal carcinogenesis.
 ...
PMID:Lack of involvement of nucleotide excision repair gene polymorphisms in colorectal cancer. 1286 26


1 2 3 Next >>