Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 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.
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PMID:Xeroderma pigmentosum and molecular cloning of DNA repair genes. 868 16

The xeroderma pigmentosum group G (XP-G) gene (XPG) encodes a structure-specific DNA endonuclease that functions in nucleotide excision repair (NER). XP-G patients show various symptoms, ranging from mild cutaneous abnormalities to severe dermatological impairments. In some cases, patients exhibit growth failure and life-shortening and neurological dysfunctions, which are characteristics of Cockayne syndrome (CS). The known XPG protein function as the 3' nuclease in NER, however, cannot explain the development of CS in certain XP-G patients. To gain an insight into the functions of the XPG protein, we have generated and examined mice lacking xpg (the mouse counterpart of the human XPG gene) alleles. The xpg-deficient mice exhibited postnatal growth failure and underwent premature death. Since XPA-deficient mice, which are totally defective in NER, do not show such symptoms, our data indicate that XPG performs an additional function(s) besides its role in NER. Our in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the early onset of immortalization and accumulation of p53.
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PMID:Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene. 1002 22

Ionizing radiation-induced stabilization and the resultant transient accumulation of the p53 tumor suppressor protein is impaired in cells from ataxia telangiectasia (AT) patients, indicating a key role for ATM, the gene mutated in AT, upstream in the radiation-responsive p53 signaling pathway. Activation of this pathway is generally assumed to be triggered by DNA strand breaks produced directly following genotoxic stress or indirectly during excision repair of DNA lesions. The aim of this study was to identify the triggering signal for induction of p53 in diploid human dermal fibroblasts treated with 4-nitroquinoline 1-oxide (4NQO), a model environmental carcinogen that produces both DNA strand breaks (like ionizing radiation) and alkali-stable bulky DNA lesions (like UV light). 4NQO treatment of fibroblasts cultured from normal and AT donors and those from patients with the UV-hypersensitivity disorder xeroderma pigmentosum (XP, complementation groups A, E and G) resulted in up-regulation of p53 protein. In normal fibroblasts, there was no temporal relationship between the incidence of DNA strand breaks and levels of p53 protein; >90% of strand breaks and alkali-labile sites were repaired over 2 h following treatment with 1 microM 4NQO, whereas approximately 3 h of post-treatment incubation was required to demonstrate a significant rise in p53 protein. In contrast, exposure of normal fibroblasts to gamma-rays resulted in a rapid up-regulation of p53 and the level peaked at 2 h post-irradiation. XP cells with a severe deficiency in the nucleotide excision repair pathway showed abnormally high levels of p53 protein in response to 4NQO treatment, indicating that lesions other than incision-associated DNA strand breaks trigger p53 up-regulation. We observed a consistent, inverse correlation between the ability of the various fibroblast cultures to induce p53 following 4NQO treatment and their DNA repair efficiencies. Treatment with 0.12 microM 4NQO, for example, caused a >2-fold up-regulation of p53 in excision repair-deficient (AT, XPA and XPG) strains without eliciting any effect on p53 levels in repair-proficient (normal and XPE) strains. We conclude that up-regulation of p53 by 4NQO is mediated solely by an ATM-independent mechanism and that the p53 response is primarily triggered by persistent alkali-stable 4NQO-DNA adducts.
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PMID:Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response. 1035 71

We have previously reported on mRNA expression of ERCC1, XPA and XPD in human ovarian cancer cells and tissues. Several factors can influence mRNA expression for any given gene. Alterations in gene copy number for ERCC1 and/or XPD have been reported to occur in malignant glioma specimens. Human ovarian cancer cell lines and tissues were therefore examined for evidence of altered gene copy number in selected genes within the nucleotide excision repair (NER) pathway. Six ovarian cancer cell lines were studied: A2780, A2780/CP70, SKOV3, MCAS, QvCar3 and Caov4. Cellular sensitivity to cisplatin varies by more than 1 log between some of these cells. In each of these cell lines, the genes examined included ERCC1, XPA, XPB, XPD, XPG, CSB and p53. Genomic DNA was also extracted from ovarian cancer specimens taken from 22 patients and assessed for evidence of allelic loss and/or allelic gain for ERCC1 and XPD. Twelve of the clinical specimens were from patients with platinum-sensitive tumors and ten were from patients with platinum-resistant tumors. In no case could we demonstrate a reproducible variation in gene copy number in any cell line. Among the human tissues studied, there was one case of allelic gain out of 22 specimens. We therefore conclude that alterations in gene copy number is not a common event in human ovarian cancer. Other mechanisms must be invoked to explain differences in mRNA expression for these genes.
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PMID:Absence of evidence for allelic loss or allelic gain for ERCC1 or for XPD in human ovarian cancer cells and tissues. 1073 6

In the 30 years since the introduction of cisplatin into the clinic, laboratory studies have provided considerable information as to both how the drug exerts its antitumour effects and how some tumours are, or become, resistant. Once inside a cell, the chlorine groups of cisplatin are exchanged for water (aqua) species, which are more chemically reactive. The intracellular target for cisplatin is DNA, where a variety of adducts are formed, some on the same strand of DNA (intrastrand adducts) and others between strands (interstrand adducts). Of the 4 bases, guanine is the preferred site for binding and the most common adduct involves linkages on 2 adjacent guanines on the same strand of DNA. It remains uncertain which of the various types of adduct is the most important in terms of producing antitumour effects. Resistance to cisplatin has been studied extensively using tumour cells repeatedly exposed to the drug in vitro. In these cell models, resistance is generally due to a combination of mechanisms, some resulting in reduced damage to DNA and others following DNA damage. Resistance due to inadequate binding to DNA has been shown to be caused by reduced drug uptake (influx rather than efflux) and inactivation by thiol-containing species such as glutathione and metallothioneins. Resistance occurring post-DNA binding may be due to changes in DNA repair pathways [an increase in nucleotide excision repair (NER) or a loss of DNA mismatch repair (MMR)]. Conversely, the hypersensitivity of some cell lines to cisplatin has been shown to be due to defective NER, through loss or reduced expression of NER proteins such as XPG and XPA. Resistance may also be mediated through alterations in proteins involved in programmed cell death (apoptosis) such as p53 and the BCL2 family. A basic understanding of cisplatin resistance pathways has made a major impact in the development of new platinum analogues capable of circumventing resistance. Examples (which are now undergoing clinical trial) include ZD0473 (which, relative to cisplatin, possesses a reduced reactivity towards inactivating thiol-containing molecules) and the trinuclear platinum BBR3464 (which has markedly different DNA binding properties compared with cisplatin).
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PMID:Preclinical perspectives on platinum resistance. 1086 25

The contribution of DNA strand breaks accumulating in the course of nucleotide excision repair to upregulation of the p53 tumor suppressor protein was investigated in human dermal fibroblast strains after treatment with 254 nm ultraviolet (UV) light. For this purpose, fibroblast cultures were exposed to UV and incubated for 3 h in the presence or absence of l-beta-D-arabinofuranosylcytosine (araC) and/or hydroxyurea (HU), and then assayed for DNA strand breakage and p53 protein levels. As expected from previous studies, incubation of normal and ataxia telangiectasia (AT) fibroblasts with araC and HU after UV irradiation resulted in an accumulation of DNA strand breaks. Such araC/HU-accumulated strand breaks (reflecting nonligated repair-incision events) following UV irradiation were not detected in xeroderma pigmentosum (XP) fibroblast strains belonging to complementation groups A and G. Western blot analysis revealed that normal fibroblasts exhibited little upregulation of p53 (approximately 1.2-fold) when incubated without araC after 5 J/m2 irradiation, but showed significant (three-fold) upregulation of p53 when incubated with araC after irradiation. AraC is known to inhibit nucleotide excision repair at both the damage removal and repair resynthesis steps. Therefore, the potentiation of UV-induced upregulation of p53 evoked by araC in normal cells may be a consequence of either persistent bulky DNA lesions or persistent incision-associated DNA strand breaks. To distinguish between these two possibilities, we determined p53 induction in AT fibroblasts (which do not upregulate p53 in response to DNA strand breakage) and in XP fibroblasts (which do not exhibit incision-associated breaks after UV irradiation). The p53 response after treatment with 5 J/m2 UV and incubation with araC was similar in AT, XPA, XPG and normal fibroblasts. In addition, exposure of XPA and XPG fibroblasts to UV (5, 10 or 20 J/m2) followed by incubation without araC resulted in a strong upregulation of p53. We further demonstrated that HU, an inhibitor of replicative DNA synthesis (but not of nucleotide excision repair), had no significant impact on p53 protein levels in UV irradiated and unirradiated human fibroblasts. We conclude that upregulation of p53 at early times after exposure of diploid human fibroblasts to UV light is triggered by persistent bulky DNA lesions, and that incision-associated DNA strand breaks accumulating in the course of nucleotide excision repair and breaks arising as a result of inhibition of DNA replication contribute little (if anything) to upregulation of p53.
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PMID:Lack of correlation between DNA strand breakage and p53 protein levels in human fibroblast strains exposed to ultraviolet lights. 1104 30

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.
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PMID:Loss of heterozygosity of nucleotide excision repair factors in sporadic oral squamous cell carcinoma using microdissected tissue. 1149 30

The deficiencies of nucleotide excision repair (NER) factors are genetic diseases, xeroderma pigmentosum (XP) increasing 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 for the XP, XPA, XPB, XPC, XPD, XPE, XPF, XPG and the transcription-coupled repair factor, Cockayne syndrome B (CSB) revealed that NER factors were abnormal in 62.1 % of ovarian tumors (18/29), 16.7% of colon (2/12) and 22.2% lung (2/9) carcinomas. Furthermore, 13.8% of ovarian, 8.3% of colon and 22% of lung carcinomas exhibited LOH for NER factors without LOH for tumor suppressor genes such as p53, FHIT, APC, BRCAI, BRCA2 and DCC. Although both microsatellite instability and LOH of NER factors were observed in some cases, there was no strong association between them in the present study. These observations raise the possibility that alterations of NER factors may be frequent in human sporadic carcinomas. Further study should be needed to find the direct evidence of NER gene abnormalities in human sporadic carcinoma tissues.
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PMID:Loss of heterozygosity of nucleotide excision repair factors in sporadic ovarian, colon and lung carcinomas: implication for their roles of carcinogenesis in human solid tumors. 1168 86

Functional tumor suppressor p53 is mainly required for efficient global genomic repair (GGR), a subpathway of nucleotide excisions repair (NER). In this study, the regulatory effect of p53, on the spaciotemporal recruitment of XPC and TFIIH to DNA damage sites, was investigated in repair-proficient and -deficient human cells in situ. Photoproducts were induced through micropore UV irradiation of discrete subnuclear areas of intact cells and the specific lesions, as well as recruited repair factors, were detected by immunofluorescent intensity and density of the damaged DNA subnuclear spots (SNS). Both cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4PP) were visualized in situ at SNS within irradiated nuclear foci. The in situ repair kinetics revealed that p53-WT normal fibroblasts are proficient for the repair of both CPD and 6-4PP, whereas, p53-Null Li-Fraumeni syndrome (LFS) fibroblasts fail to efficiently repair CPD but not 6-4PP. Colocalization experiments of the NER factors showed that in normal human cells, XPC and TFIIH are rapidly and efficiently recruited to DNA damage within SNS. By contrast, recruitment of both XPC and TFIIH to DNA damage in SNS occurred much less efficiently in p53-Null or p53-compromised cells. The total cellular levels of XPC and XPB were similar in both p53-WT and -Null cells and remained unchanged up to 24h following UV irradiation. The results also showed that dispersal of recruited XPC and TFIIH from DNA damage SNS occurs within a short period after DNA damage. Such dispersal requires functional XPA, XPF and XPG proteins. Taken together, the results demonstrated that p53 plays a pronounced role in the damage recognition and subsequent assembly of repair machinery during GGR and the recruitment of XPC and TFIIH to CPD is p53-dependent. Most likely mechanism of this p53 action is through its downstream effector protein, DDB2.
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PMID:Tumor suppressor p53 dependent recruitment of nucleotide excision repair factors XPC and TFIIH to DNA damage. 1271 9

Thymine glycol (Tg) is one of predominant oxidative DNA lesions caused by ionizing radiation and other oxidative stresses. Human NTH1 is a bifunctional enzyme with DNA glycosylase and AP lyase activities and removes Tg as the first step of base excision repair (BER). We have searched for the factors interacting with NTH1 by using a pull-down assay and found that GST-NTH1 fusion protein precipitates proliferating cell nuclear antigen (PCNA) and p53 as well as XPG from human cell-free extracts. GST-NTH1 also bound to recombinant FLAG-tagged XPG, PCNA, and (His)6-tagged p53 proteins, indicating direct protein-protein interaction between those proteins. Furthermore, His-p53 and FLAG-XPG, but not PCNA, stimulated the Tg DNA glycosylase/AP lyase activity of GST-NTH1 or NTH1. These results provide an insight into the positive regulation of BER reaction and also suggest a possible linkage between BER of Tg and other cellular mechanisms.
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PMID:Human NTH1 physically interacts with p53 and proliferating cell nuclear antigen. 1535 33


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