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PubMed2000

Interrelationships between cellular nucleotide excision repair, cisplatin cytotoxicity, HER-2/neu gene expression, and epidermal growth factor receptor level in non-small cell lung cancer cells.

Nucleotide excision repair (NER) is a major repair mechanism for DNA lesions induced by cisplatin. Overexpressions of epidermal growth factor receptor (EGFR) and HER-2/neu have been reported to affect the sensitivity of certain human cancer cells to cisplatin, presumably by modification of DNA repair activity through interference with NER. Using an in vitro repair assay, we investigated NER activity of cisplatin-induced DNA lesions in a panel of 16 non-small cell lung cancer (NSCLC) cell lines. The interrelationships between NER activity, cisplatin sensitivity, HER-2/neu expression and EGFR level, were also analyzed. The results showed that high NER activity was closely correlated with cisplatin resistance and high levels of HER-2/neu expression (P<0.05). Analysis of the relationships between EGFR level and each of the other three parameters revealed no statistically significant correlations (all P values were >0.05 by Spearman rank correlation), but a trend of association (all the values of proportion of accordance were > or =62.5% by using a 2x2 contingency table). These results suggest that NER activity may play an important role in the cisplatin resistance of NSCLC cells and there may be an association between enhanced NER activity and high levels of p185neu and probably EGFR in NSCLC cells. The finding that high levels of EGFR showed very little influence on the relationship between p185neu and cisplatin resistance suggests that EGFR may be a less crucial factor in modulating the chemoresistance of NSCLC cells when compared with HER-2/neu.

Antineoplastic Agents↗

PubMed1991

DNA polymerase delta mediates excision repair in growing cells damaged with ultraviolet radiation.

In confluent, stationary phase cells, an aphidicolin-sensitive DNA polymerase mediates UV-induced excision repair, but the situation in growing cells is still controversial. The sensitivity of repair synthesis to aphidicolin, an inhibitor of DNA polymerases alpha and delta, was determined in growth phase and confluent normal human fibroblasts (AG1518) using several techniques. Repair synthesis in confluent cells was always inhibited by aphidicolin, no matter which measurement technique was used. However, the inhibition of repair synthesis in growth-phase cells by aphidicolin was only detectable when techniques unaffected by changes in nucleotide metabolism were used. We conclude that UV-induced repair synthesis in growing cells is actually aphidicolin sensitive, but that this inhibition can be obscured by changes in nucleotide metabolism. Employing butylphenyl-deoxyguanosine triphosphate, a potent inhibitor of polymerase alpha and a weak inhibitor of delta, we have obtained evidence that polymerase delta is responsible for repair synthesis in growth-phase cells following UV irradiation.

Aphidicolin↗

PubMed2005

Expression of nucleotide excision repair proteins in lymphocytes as a marker of susceptibility to squamous cell carcinomas of the head and neck.

The transcript levels of nucleotide excision repair (NER) genes were shown to be associated with risk of squamous cell carcinomas of the head and neck (SCCHN). However, this association may be biased, because the transcript level does not necessarily reflect the level of protein expression. To address this issue, we did a pilot study to test the hypothesis that the expression of six core NER proteins is associated with risk of SCCHN. We obtained cultured lymphocytes from 57 patients with newly diagnosed SCCHN patients and 63 cancer-free controls. We transfected some of the lymphocytes with both damaged and undamaged plasmid DNA and quantified NER protein levels in these lymphocytes using a reverse-phase protein microarray. The relative NER protein levels in the 63 controls were highly correlated with each other (P<0.001 for all). Compared with the controls, the cases had lower expression levels for all the NER proteins, particularly XPC and XPF, which were reduced by about 25% (P<0.01). When we used the median expression levels of the NER proteins in the controls as cutoff values, we found that a significantly increased risk of SCCHN was associated with low expression of XPA [odds ratio (OR), 2.99; 95% confidence interval (CI), 1.22-7.47], XPC (OR, 2.46; 95% CI, 1.04-5.87), XPD (OR, 3.02; 95% CI, 1.18-7.76), and XPF (OR, 5.29; 95% CI, 2.01-13.9), but not ERCC1 and XPG, after adjustment for age, sex, ethnicity, smoking, alcohol use, and sample storage time. In a multivariate logistic regression model that included all covariates and NER proteins, however, only low expression of XPF remained a significant risk factor for SCCHN (OR, 11.5; 95% CI, 2.32-56.6). These results suggest that XPF may be a crucial rate-limiting factor in DNA repair and that the reverse-protein microarray assay may be a useful tool for measuring protein markers of susceptibility to cancer.

Biomarkers, Tumor↗

PubMed2003

Imbalancing the DNA base excision repair pathway in the mitochondria; targeting and overexpressing N-methylpurine DNA glycosylase in mitochondria leads to enhanced cell killing.

The DNA base excision repair (BER) pathway is responsible for the repair of alkylation and oxidative DNA damage. The short-patch BER pathway, beginning with the simple glycosylase N-methylpurine DNA glycosylase (MPG), is responsible for the removal of damaged bases such as 3-methyladenine and 1,N(6)-ethenoadenine from the DNA after alkylation or oxidative DNA damage. The resulting apurinic site is further processed by the other members in the pathway, resulting in the insertion of the correct nucleotide. If apurinic sites accumulate, they are mutagenic and cytotoxic to the cell. To evaluate its efficacy in sensitizing breast cancer cells to chemotherapy, MPG has been overexpressed in the breast cancer cell line, MDA-MB231. With MPG overexpression, an increase in DNA damage and increased cytotoxicity to methyl methanesulfonate as well as increased apoptosis levels was observed in these cells. Because mitochondrial DNA has been shown to be more sensitive to DNA damage than nuclear DNA, a construct containing mitochondrial-targeted MPG using the human manganese superoxide dismutase mitochondrial-targeting sequence was made. Overexpression of the mitochondrially targeted MPG dramatically increased the breast cancer cells' sensitivity to methyl methanesulfonate. In conclusion, we believe that the increase in sensitivity to DNA damage by overexpression of nuclear MPG is because of an imbalance in the BER pathway, and an even greater increase in cell sensitivity is observed when mitochondrial DNA is targeted.

Annexin A5↗

PubMed1992

Post-incision steps of nucleotide excision repair in Escherichia coli. Disassembly of the UvrBC-DNA complex by helicase II and DNA polymerase I.

UvrA, UvrB, and UvrC initiate nucleotide excision repair by incising a damaged DNA strand on each side of the damaged nucleotide. This incision reaction is substoichiometric with regard to UvrB and UvrC, suggesting that both proteins remain bound following incision and do not "turn over." The addition of only helicase II to such reaction mixtures turns over UvrC; UvrB turnover requires the addition of helicase II, DNA polymerase I, and deoxynucleoside triphosphates. Column chromatography and psoralen photocross-linking experiments show that following incision, the damaged oligomer remains associated with the undamaged strand, UvrB, and UvrC in a post-incision complex. Helicase II releases the damaged oligomer and UvrC from this complex, making repair synthesis possible; DNase I footprinting experiments show that UvrB remains bound to the resulting gapped DNA until displaced by DNA polymerase I. The specific binding of UvrB to a psoralen adduct in DNA inhibits psoralen-mediated DNA-DNA cross-linking, yet promotes the formation of UrvB-psoralen-DNA cross-links. The discovery of psoralen-UvrB photocross-linking offers the potential of active-site labeling.

Adenosine Triphosphatases↗

PubMed2005

[Enhancement effect of nucleotide excision repair gene xeroderma pigmentosun group a antisense RNA on sensitivity of human lung adenocarcinoma cell line A549 to cisplatin].

BACKGROUND & OBJECTIVE: Enhanced nucleotide excision repair (NER) capacity is an important mechanism of drug-resistance of tumor cells. Xeroderma pigmentosun group A (XPA) gene plays a key role in early stage of NER pathway. This study was to explore correlation between down-regulation of XPA gene induced by antisense RNA transfection and sensitivity of human lung adenocarcinoma cell line A549 to cisplatin. METHODS: A549 cells were stably transfected with XPA antisense RNA. Positive cell clones were selected by limiting dilution. Northern blot and Western blot were applied to evaluate mRNA and protein levels of XPA in positive cell clones. Sensitivity of A549 cells to cisplatin was evaluated by MTT assay. Host cell reactivation (HCR) assay was used to assess NER capacity of cisplatin-damaged A549 cells. RESULTS: Six positive cell clones, AS1-AS6, were obtained, mRNA and protein levels of XPA were significantly decreased in AS3-AS6 cells. In dose-dependent experiment, the 50% inhibitory concentrations (IC(50)) of cisplatin to parental A549 cells and AS1-AS6 cells were 8.1, 7.6, 4.7, 3.2, 1.9, 2.8, and 4.1 mug/ml, respectively. Sensitivities of AS3-AS6 cells were significantly higher than that of parental A549 cells (F = 9.75, 9.14, 7.39, 8.91u P = 0.005, 0.006, 0.012, 0.006). In addition, mRNA level of XPA was positively correlated with IC(50) of cisplatin (r = 0.927, P = 0.003). Time-effect experiment also showed increases of sensitivity to cisplatin in AS3-AS6 cells. HCR assay showed that NER capacities of AS3-AS6 cells were reduced. When treated with 40, 200, and 1 000 ng/ml of cisplatin, mRNA levels of XPA were positively correlated with cellular NER capacities (r = 0.854, 0.696, 0.858u P = 0.014, 0.082, 0.013). CONCLUSION: The targeted inhibition of XPA by antisense strategy can significantly decrease mRNA level of XPA, reduce cellular NER capacity, and sensitize lung cancer cells to cisplatin.

Adenocarcinoma↗

PubMed1991

Atomic structure of a pyrimidine-dimer specific excision-repair enzyme from bacteriophage T4.

T4 endonuclease V is an enzyme responsible for the first step of a pyrimidine-dimer specific excision-repair process. The three-dimensional structure of this enzyme has been determined at 1.6A resolution by X-ray crystallography. The enzyme consists of one single compact domain classified into the all alpha structure. This single domain possesses two distinct catalytic activities, a pyrimidine-dimer glycosylase and an apurinic/apyrimidinic endonuclease. The backbone of the enzyme represents a unique folding scheme incompatible with close packing of alpha-helices. The refined structure suggests possible residues that participate in interactions with DNA.

Amino Acid Sequence↗

PubMed1999

Use of novel plasmid constructs to demonstrate fludarabine triphosphate inhibition of nucleotide excision repair of a site-specific 1,2-d(GpG) intrastrand cisplatin adduct.

We previously showed that fludarabine triphosphate (F-ara-ATP) acts as a potent inhibitor of nucleotide excision repair (NER). To determine how F-ara-ATP inhibits NER, we designed closed circular DNA duplexes, each containing a site-specific d(GpG) cisplatin adduct, as the substrate for an in vitro repair assay. We used the assay to determine the effects of F-ara-ATP on the incision, repair synthesis, and ligation steps in the NER process. A closed circular DNA duplex, pSSA, was first constructed by inserting an 87-bp oligonucleotide into pGEM-7Zf(+), from which a single-stranded plasmid (pTDS) was derived. The 87-bp insert included two potential repair patches; each contained a d(GpG) site flanked by unique sequences 22 nucleotides upstream and 6 nucleotides downstream so that four dAMP sites were strategically placed in patch 1 but were absent from patch 2. Each duplex substrate was then synthesized by annealing a unique primer containing a platinated and 32P-end-labeled oligonucleotide to the pTDS template, which was then converted to a duplex through polymerization and ligation. At 50 microM, F-ara-ATP inhibited repair synthesis; F-ara-ATP also inhibited incision and ligation, but only at concentrations of 200 microM and above. Chemical DNA sequencing of the repair patch revealed that F-ara-ATP induced the formation of a truncated repair patch in which DNA polymerization stopped one nucleotide before the first installed dAMP site - a potential site for F-ara-ATP's incorporation. In contrast, truncation of a repair patch was not detectable when the repair patch contained no dAMP. Taken together, the results suggest that F-ara-ATP induced patch truncation by self-incorporation and the incorporated F-ara-AMP was subsequently excised, presumably by polymerase-associated exonuclease activity. We conclude that F-ara-ATP blocks the NER process by strongly inhibiting DNA repair synthesis as well as by less strongly inhibiting incision and ligation. Our approach of designing plasmid constructs that contain sequence-specific repair patches with a strategically placed 32P label may provide a powerful tool for dissecting the mechanism of NER inhibition not only for F-ara-ATP but also for other NER inhibitors.

Adenosine Triphosphate↗

PubMed1998

Human nucleotide excision repair protein XPA: extended X-ray absorption fine-structure evidence for a metal-binding domain.

The ubiquitous, multi-enzyme, nucleotide excision repair (NER) pathway is responsible for correcting a wide range of chemically and structurally distinct DNA lesions in the eukaryotic genome. Human XPA, a 31 kDa, zinc-associated protein, is thought to play a major NER role in the recognition of damaged DNA and the recruitment of other proteins, including RPA, ERCC1, and TFIIH, to repair the damage. Sequence analyses and genetic evidence suggest that zinc is associated with a C4-type motif, C105-X2-C108-X17-C126-X2-C129, located in the minimal DNA binding region of XPA (M98-F219). The zinc-associated motif is essential for damaged DNA recognition. Extended X-ray absorption fine structure (EXAFS) spectra collected on the zinc associated minimal DNA-binding domain of XPA (ZnXPA-MBD) show directly, for the first time, that the zinc is coordinated to the sulfur atoms of four cysteine residues with an average Zn-S bond length of 2.34+/-0.01 A. XPA-MBD was also expressed in minimal medium supplemented with cobalt nitrate to yield a blue-colored protein that was primarily (>95%) cobalt associated (CoXPA-MBD). EXAFS spectra collected on CoXPA-MBD show that the cobalt is also coordinated to the sulfur atoms of four cysteine residues with an average Co-S bond length of 2.33+/-0.02 A.

Absorptiometry, Photon↗

PubMed1998

Nucleotide excision repair is not required for the antiapoptotic function of insulin-like growth factor 1.

The expression of ERCC1, a member of the nucleotide excision repair (NER) family, is enhanced in cells transfected with insulin-like growth factor 1 (IGF-1) receptors. Of interest, an excellent concordance between ERCC1 expression and NER-mediated cell survival has been demonstrated. The two aims of the present study were to determine the signaling pathways used by IGF-1 to confer protection against apoptotic cell death in Chinese hamster ovary (CHO) cells and to assess the role of NER in this IGF-1 action. Experiments with pharmacological inhibitors indicated that phosphatidylinositol 3-kinase (PI 3-kinase) but not mitogen-activated protein kinase (ERK1/ERK2) mediates IGF-1 antiapoptotic activity. Using two series of CHO cells that have altered expression of ERCC1 or XPB/ERCC3, we examined IGF-1's ability to delay apoptotic death and reduction of mitochondrial oxidative function mediated by growth factor withdrawal. IGF-1 effectively blocked apoptosis, concomitant with increased MTT activity, in a pair of CHO cell lines expressing inactive ERCC1 (43-3B cells) and the transfected line of the mutant carrying the expressed human ERCC1 gene (83-G5 cells). Similarly, repair-deficient UV24 cells, which lack XPB/ERCC3, and their parental line AA8 were also responsive to the IGF-1's antiapoptotic capacity. In the presence of IGF-1, these cell lines became resistant to the cleavage of poly(ADP-ribose) polymerase, a key player in DNA damage recognition and DNA repair. These results suggest that PI 3-kinase activation plays a determinant role in the antiapoptotic function of IGF-1, but that functional NER does not play a critical part in mediating this IGF-1 response.

Animals↗

PubMed1981

Mutants partially defective in excision repair at five autosomal loci in Drosophila melanogaster.

Primary cell cultures derived from mutants in seventeen different genes were analyzed for their ability to excise pyrimidine dimers from DNA. Five of these mutagen-sensitive mutants [mus(2)205A1, mus(3)302D1, mus(3)304D3, mus(3)306D1, mus(3)308D2] display a significantly reduced excision capacity relative to control cultured. In addition, two of the five [mus(3)306D2, mus(3)308D2] are defective in the accumulation of single-strand breaks normally seen after ultraviolet irradiation. This study, therefore, brings the total number of Drosophila mutants known to be defective in excision repair to seven. The results are discussed relative to other genetic and biochemical properties of these mutants.

Animals↗

PubMed1989

Excision repair differences in rat fibroblasts.

By using a cellular transformation system, which has been developed by Graffi et al., we analysed differences in the excision capacity of UV-induced dimers in normal cells, in vitro transformed cells and in malignant cells derived from a rat fibrosarcoma. The results suggest that both the transformed and the tumour-derived cells exhibit a kinetic pattern of excision repair different from that of the normal cells. Recognition of the dimers and the incision rate are more complete in the normal cell.

Animals↗

PubMed2003

Hepatitis B virus X protein does not influence essential steps of nucleotide excision repair effected by human liver extracts.

The X protein (HBx) of hepatitis B virus (HBV) is thought to compromise TFIIH function during hepatocyte nucleotide excision repair (NER) to cause the accumulation of hepatocarcinogenic mutations. The TFIIH holoenzyme, including XPB and XPD helicases, is absolutely required for transcription coupled (TCR) as well as global genome (GGR) NER pathways. Using an assay in which GGR carried out by extracts of foetal hepatocytes is reconstituted, we found that incisions [Formula: see text] and [Formula: see text] to a defined cisplatin DNA lesion occurred normally in the presence of functional recombinant HBx. Moreover, HBx did not significantly impair synthesis of the repair patch that completes the NER pathway. These data indicate that HBx does not directly interrupt the function of TFIIH during GGR and suggest that any HBx-mediated inhibitory effect on TFIIH is a transcription-coupled event.

Adaptor Proteins, Signal Transducing↗

PubMed2002

The carboxy-terminal domain of the XPC protein plays a crucial role in nucleotide excision repair through interactions with transcription factor IIH.

The xeroderma pigmentosum group C (XPC) protein specifically involved in genome-wide damage recognition for nucleotide excision repair (NER) was purified as a tight complex with HR23B, one of the two mammalian homologs of RAD23 in budding yeast. This XPC-HR23B complex exhibits strong binding affinity for single-stranded DNA, as well as preferential binding to various types of damaged DNA. To examine the structure-function relationship of XPC, a series of truncated mutant proteins were generated and assayed for various binding activities. The two domains participating in binding to HR23B and damaged DNA, respectively, were mapped within the carboxy-terminal half of XPC, which also contains an evolutionary conserved amino acid sequence homologous to the yeast RAD4 protein. We established that the carboxy-terminal 125 amino acids are dispensable for both HR23B and damaged DNA binding, while interactions with transcription factor IIH (TFIIH) are significantly impaired by truncation of this domain. Furthermore, deletion of the extreme carboxy-terminal domain totally abolished XPC activity in the cell-free NER reaction. These results suggest that following initial damage recognition, the carboxy terminus of XPC may be essential for the recruitment of TFIIH, and that most truncation mutations identified in XP-C patients result in non-functional proteins.

Baculoviridae↗

PubMed1974

Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species.

The ability of fibroblasts to perform unscheduled DNA synthesis (a measure of excision-repair) after UV irradiation was measured radioautographically for seven species at several times after several UV fluences. Both the initial rate and the maximum incorporation of [(3)H]dThd increased with the life-span of the species (shrew, mouse, rat, hamster, cow, elephant, man). Unscheduled DNA synthesis was approximately proportional to the logarithm of life-span.

Aging↗

PubMed2006

Arabidopsis homologue of human transcription factor IIH/nucleotide excision repair factor p44 can function in transcription and DNA repair and interacts with AtXPD.

Eukaryotic general transcription factor (TF) IIH is composed of 10 proteins, seven of which are also required for nucleotide excision repair (NER) of UV radiation-induced DNA damage in human cells and yeast. Plant homologues of the human TFIIH subunits XPB and XPD that function in NER have been isolated but none has been shown to operate in transcription. Here we address the capabilities of Arabidopsis thaliana AtGTF2H2 and AtXPD, homologues of the essential interacting human/yeast TFIIH components p44/Ssl1 and XPD/Rad3, respectively. Expression of AtGTF2H2 or AtXPD cDNAs in yeast ssl1 or rad3 mutants temperature-sensitive for growth due to thermolabile transcription of mRNA restored growth and so transcription at the non-permissive temperature. AtGTF2H2 also complemented the NER deficiency of the corresponding yeast mutant, as measured by full recovery of UV resistance, whereas AtXPD did not despite being necessary for NER in Arabidopsis. UV treatment did not upregulate transcription of AtGTF2H2 or AtXPD in Arabidopsis. Suppression of a yeast translation initiation defect by the ssl1-1 mutation was prevented by expression of AtGTF2H2. Deletion of SSL1 in a yeast strain expressing AtGTF2H2 did not affect growth or confer UV sensitivity, demonstrating that AtGTF2H2 can perform all essential transcription functions and UV damage repair duties of Ssl1 in its absence. Furthermore, AtGTF2H2 interacted with AtXPD and yeast Rad3, and AtXPD also interacted with yeast Ssl1 in two-hybrid assays. Our results indicate that AtGTF2H2 can act in transcription and NER, and suggest that it participates in both processes in Arabidopsis as part of TFIIH.

Adenosine Triphosphatases↗

PubMed2001

Nucleotide excision repair gene expression in the rat conceptus during organogenesis.

DNA repair may be a determinant of the susceptibility of the conceptus to DNA damaging teratogens. The nucleotide excision repair (NER) pathway repairs a substantial amount of chemically induced DNA damage. The goals of this study were to assess the coordinate expression of NER genes in the midorganogenesis-stage rat conceptus and determine the consequences of exposure to the genotoxic teratogen, 4-hydroperoxycyclophosphamide (4-OOHCPA), on NER gene expression. Most NER genes were expressed at low levels in both yolk sac and embryo on gestational day (GD) 10, with the exception of XPD, XPE and PCNA. No significant alterations in gene expression occurred between GDs 10 and 11; in the yolk sac XPB expression increased on GD12 compared to either GD10 or 11. In the embryo, XPE expression increased between GDs 10 and 12, while hHR23B, XPB, ERCC1, and DNA polymerase epsilon expression increased on GD12 relative to both GDs 10 and 11. Contrary to gene expression data, XPB protein was found at high levels and XPD at low levels in GDs 10-12 embryos and yolk sacs. Mirroring gene expression, high levels of PCNA protein were found in both tissues; XPA protein levels were minimal in yolk sac from GDs 10-12 but increased in the embryo from moderate on GD10 to high on GD12. Therefore, NER gene expression during organogenesis was regulated in a developmental stage- and tissue-specific manner. Exposure of the conceptus to a teratogen, 4-OOHCPA, induced malformations without affecting NER transcript levels. Thus, NER gene expression in the conceptus was unresponsive to regulation by DNA alkylation.

Animals↗

PubMed2002

Polymorphisms in the human xeroderma pigmentosum group A gene and their impact on cell survival and nucleotide excision repair.

Polymorphisms in DNA repair genes may contribute to defects in DNA repair and increased susceptibility to cancer. The xeroderma pigmentosum group A (XPA) gene is required for nucleotide excision repair (NER) and mutations in XPA highly predispose humans to skin cancer. We examined DNA samples from 189 individuals for polymorphisms in the XPA gene. First, SSCP analysis was used to examine each of the six exons and their intron boundaries. One frequent single nucleotide polymorphism (SNP) in the untranslated region of exon 1 and two rare SNPs which produce the changes Arg228Gln and Val234Leu in the coding region of exon 6 were identified. Quite surprisingly, no sequence variants were found within the coding regions or the adjacent intron boundaries of exons 1-5. Ecdysone-inducible expression vectors containing wild type XPA cDNA or cDNAs representing the two polymorphisms that we identified in exon 6 were created and independently introduced into the XPA deficient cell line XP12RO-SV. Transcription-coupled repair (TCR), global genome repair (GGR) and cell survival following UV irradiation were studied in each cell line in the absence or presence of the ecdysone hormone analog, ponasterone A. No substantial difference in repair or cell survival was found in cells complemented with wild type or polymorphic alleles of XPA. A 10-fold increase in the expression of XPA by addition of ponasterone A resulted in faster removal of 6-4 photoproducts from the total genomes of cells complemented with wild type or polymorphic alleles of XPA but had no significant impact on TCR or global genome repair of cyclobutane pyrimidine dimers (CPDs). Since our SSCP analysis failed to detect significant numbers of polymorphisms we directly sequenced exons 4-6 in a subset of our samples. One additional rare SNP, which produces the change Leu252Val was found in exon 6 and four rare SNPs and one rare single nucleotide deletion were found in intron 4. Hence, the XPA gene appears to be a cold spot for genetic variation and rare polymorphisms in the coding region of the gene do not reduce NER or cell survival after UV irradiation.

Cell Survival↗