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

Molecular profiling of markers involved in the activity of chemotherapeutic agents can shed light on the successes and failures of treatment in patients and can also provide a basis for individualization of therapy. Toward those ends, we have used reverse-phase protein lysate microarrays to evaluate expression of protein components of the nucleotide excision repair (NER) pathways. Those pathways strongly influence the anticancer activities of numerous drugs, including those that are the focus here, cisplatin and ecteinascidin 743 (Et-743; Yondelis, Trabectedin). Cisplatin is generally more active in cell types deficient in NER, whereas Et-743 tends to be less active in those cells. We measured protein expression and sensitivity to those drugs in 17 human ovarian and colon cancer cell lines (13 of them from the NCI-60 panel) and five xeroderma pigmentosum (XP) patient cell types, each containing a different NER defect. Of the NER proteins giving reliable signals, XPF and XPG showed the highest correlations of protein expression with drug activity across all three tissue-of-origin groups. When we compared protein expression data with mRNA expression data from Affymetrix U133A chips, we found no consistent correlation between the two across the cell lines studied, which reinforces the conclusion that protein measurements can give more interpretable mechanistic information than can transcript measurements. The work reported here provides motivation for larger proteomic studies with more cell types focused on potential biomarkers in additional pharmacologically pertinent pathways.
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PMID:Predicting cisplatin and trabectedin drug sensitivity in ovarian and colon cancers. 1818 10

Patients with xeroderma pigmentosum (XP) have a 1,000-fold increase in ultraviolet (UV)-induced skin cancers while trichothiodystrophy (TTD) patients, despite mutations in the same genes, ERCC2 (XPD) or ERCC3 (XPB), are cancer-free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV-induced 6-4 photoproducts (6-4PP) in their DNA and low levels of the basal transcription factor, TFIIH. We examined seven XP, TTD, and XP/TTD complex patients and identified mutations in the XPD gene. We discovered large differences in nucleotide excision repair (NER) protein recruitment to sites of localized UV damage in TTD cells compared to XP or normal cells. XPC protein was rapidly localized in all cells. XPC was redistributed in TTD, and normal cells by 3 hr postirradiation, but remained localized in XP cells at 24-hr postirradiation. In XP cells recruitment of other NER proteins (XPB, XPD, XPG, XPA, and XPF) was also delayed and persisted at 24 hr (p<0.001). In TTD cells with defects in the XPD, XPB, or GTF2H5 (TTDA) genes, in contrast, recruitment of these NER proteins was reduced compared to normals at early time points (p<0.001) and remained low at 24 hr postirradiation. These data indicate that in XP persistence of NER proteins at sites of unrepaired DNA damage is associated with greatly increased skin cancer risk possibly by blockage of translesion DNA synthesis. In contrast, in TTD, low levels of unstable TFIIH proteins do not accumulate at sites of unrepaired photoproducts and may permit normal translesion DNA synthesis without increased skin cancer.
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PMID:Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy. 1847 Sep 33

The cytosine nucleoside analogue 2'-C-cyano-2'-deoxy-1-beta-d-arabino-pentofuranosylcytosine (CNDAC) causes DNA single-strand breaks after its incorporation into DNA. This investigation sought to determine if DNA excision repair pathways were activated to repair this damage. Neither the base excision repair nor the mismatch repair pathway seemed to be involved. Cells deficient in the CSB protein, which initiates transcription-coupled nucleotide excision repair (NER) pathway (TC-NER), exhibited increased clonogenic sensitivity to CNDAC, whereas cells deficient in XPC, which initiates global genome NER, were slightly resistant relative to wild-type cells. The cells lacking either helicase XPB, which unwinds 5' of the lesion, or endonuclease XPF, which incises 5' to a lesion, exhibited increased clonogenic sensitivity to CNDAC, as did cells lacking the XPF partner protein ERCC1. This sensitization was independent of p53 function. Repletion of XPF restored sensitivity comparable with the wild type. In contrast, cells lacking either XPD, the 3'-helicase, or the 3'-endonuclease XPG were equally as sensitive as wild-type cells. In comparison, cells deficient in XPF were not sensitized to other cytosine nucleoside analogues, troxacitabine and cytarabine. Thus, the single-strand nick caused by CNDAC is recognized and, in part, repaired by the TC-NER pathway. NER proteins that function in the 5' direction relative to the UV-induced lesion also participate in the repair of the CNDAC-induced nick, in contrast to proteins that process on the 3' side of the lesion.
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PMID:Repair of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine-induced DNA single-strand breaks by transcription-coupled nucleotide excision repair. 1848 73

The problem of toxicity of cyanobacterial toxins is of increasing concern, as the incidence of such blooms grows. Among the toxins, the most abundant in the environment are hepatotoxins known as nodularins and microcystins. These toxins are responsible for almost all known cases of fresh and brackish water intoxication and are responsible for recurrent episodes of human and animal illness and death. Moreover, they are believed to be potent tumor promoters and initiators. However, the mechanisms by which these toxins induce liver cancer are not well understood. The aim of the present study was to determine the effect of nodularin on the kinetics of nucleotide excision repair (NER) in Chinese hamster ovary (CHO) cells exposed to UV radiation. The first set of experiments was performed to define the optimal treatment conditions for nodularin to avoid the possibility of encountering false positive signals in the comet assay due to the apoptogenic activity of nodularin. Based on the analysis of apoptosis, the 6-h treatment time of cells with nodularin (1mug/ml, 10mug/ml and 20mug/ml) was chosen for the alkaline comet assay. The kinetics of NER was determined in CHO cell lines: AA8 (wild-type) and mutant cell lines: UV135 (XPG(-)), UV41 (XPF(-)) and UV20 (ERCC1(-)) exposed to 20J/m(2) UV radiation. The micronucleus assay was performed to determine a residual DNA damage in four cell lines treated with nodularin (10mug/ml) and exposed to equitoxic doses UV radiation. Radiation doses of UV producing 50% of survival for AA8, UV135, UV20 and UV41 cell lines were calculated from UV survival curves. The results show that nodularin impairs the incision/excision step of NER in CHO cells by the ERCC1/XPF inactivation and leads to an increased level of UV-induced cytogenetic DNA damage.
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PMID:Nucleotide excision repair impairment by nodularin in CHO cell lines due to ERCC1/XPF inactivation. 1851 45

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.
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PMID:Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists. 1876 34

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.
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PMID:Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk. 1902 93

Restoration of functionally intact chromatin structure following DNA damage processing is crucial for maintaining genetic and epigenetic information in human cells. Here, we show the UV-induced uH2A foci formation in cells lacking XPC, DDB2, CSA or CSB, but not in cells lacking XPA, XPG or XPF indicating that uH2A incorporation relied on successful damage repair occurring through either GGR or TCR sub-pathway. In contrast, XPA, XPG or XPF were not required for formation of gammaH2AX foci in asynchronous cells. Notably, the H2A ubiquitin ligase Ring1B, a component of Polycomb repressor complex 1, did not localize at DNA damage sites. However, histone chaperone CAF-1 showed distinct localization to the damage sites. Knockdown of CAF-1 p60 abolished CAF-1 as well as uH2A foci formation. CAF-1 p150 was found to associate with NER factors TFIIH, RPA p70 and PCNA in chromatin. These data demonstrate that successful NER of genomic lesions and prompt CAF-1-mediated chromatin restoration link uH2A incorporation at the sites of damage repair within chromatin.
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PMID:Chromatin restoration following nucleotide excision repair involves the incorporation of ubiquitinated H2A at damaged genomic sites. 1905 99

Many studies have detailed the repressive effects of DNA methylation on gene expression. However, the mechanisms that promote active demethylation are just beginning to emerge. Here, we show that methylation of the rDNA promoter is a dynamic and reversible process. Demethylation of rDNA is initiated by recruitment of Gadd45a (growth arrest and DNA damage inducible protein 45 alpha) to the rDNA promoter by TAF12, a TBP-associated factor that is contained in Pol I- and Pol II-specific TBP-TAF complexes. Once targeted to rDNA, Gadd45a triggers demethylation of promoter-proximal DNA by recruiting the nucleotide excision repair (NER) machinery to remove methylated cytosines. Knockdown of Gadd45a, XPA, XPG, XPF, or TAF12 or treatment with drugs that inhibit NER causes hypermethylation of rDNA, establishes heterochromatic histone marks, and impairs transcription. The results reveal a mechanism that recruits the DNA repair machinery to the promoter of active genes, keeping them in a hypomethylated state.
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PMID:TAF12 recruits Gadd45a and the nucleotide excision repair complex to the promoter of rRNA genes leading to active DNA demethylation. 1921 8

Nucleotide excision repair (NER) requires the coordinated sequential assembly and actions of the involved proteins at sites of DNA damage. Following damage recognition, dual incision 5' to the lesion by ERCC1-XPF and 3' to the lesion by XPG leads to the removal of a lesion-containing oligonucleotide of about 30 nucleotides. The resulting single-stranded DNA (ssDNA) gap on the undamaged strand is filled in by DNA repair synthesis. Here, we have asked how dual incision and repair synthesis are coordinated in human cells to avoid the exposure of potentially harmful ssDNA intermediates. Using catalytically inactive mutants of ERCC1-XPF and XPG, we show that the 5' incision by ERCC1-XPF precedes the 3' incision by XPG and that the initiation of repair synthesis does not require the catalytic activity of XPG. We propose that a defined order of dual incision and repair synthesis exists in human cells in the form of a 'cut-patch-cut-patch' mechanism. This mechanism may aid the smooth progression through the NER pathway and contribute to genome integrity.
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PMID:Coordination of dual incision and repair synthesis in human nucleotide excision repair. 1927 66

Benzo[a]pyrene (BaP) is a ubiquitously distributed environmental pollutant known to cause DNA damage, which may be repaired through nucleotide excision repair (NER). The significantly negative correlation between Hsp70 levels and the level of DNA damage in workers exposed to coke oven emission had been found. However, little is known about how Hsp70 modulate the DNA repair process. In a series of experiments using the human bronchial epithelia cells (16HBE) exposed to different concentrations of BaP for 24h, we measured expression of NER subunit xeroderma pigmentosum (XP) group A, C, F, G (XPA, XPC, XPF, XPG), excision repair cross-complementing 1 (ERCC1) and Hsp70, and analyzed their possible correlations. Co-localizations of Hsp70 with NER subunit were detected by confocal microscope. We found that in vitro exposure to BaP reduced cell viability in a dose-dependent manner ranging from 2 to 64 microM. Our results showed that levels of XPA, XPG and Hsp70 significantly increased at cells exposed to 1 or 2muM BaP. In addition, curve estimation showed there was a significant correlation between relative ratios of Hsp70 and XPA, XPG in cells exposed to different concentrations of BaP. Moreover, confocal microscopy demonstrated increased co-localization of Hsp70 with XPA, XPG in nuclei of cells exposed to BaP. These results suggested that Hsp70 might play a role in nucleotide excision repair. However, the mechanisms underlying this observation need further investigation.
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PMID:Correlations and co-localizations of Hsp70 with XPA, XPG in human bronchial epithelia cells exposed to benzo[a]pyrene. 1974 47


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