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

Xeroderma pigmentosum group E (XP-E) fibroblasts (XP95TO) were transformed with pSV3neo. Selection in medium containing G418 yielded 14 clones with extended life span. Following crisis, one clone was recovered that behaved in culture as an immortal cell line and was named XPET6/1. Expression of the SV40 large T antigen gene (Tag) and increased level of p53 were demonstrated by western analyses. Fingerprinting with 14 polymorphic microsatellite genetic markers confirmed that XPET6/1 originated from the parental strain XP95TO. XPET6/1 retained the sensitivity to killing by UV observed with the parental strain. Cell-free extracts from the immortal or the parental XP-E cells were deficient in excision, compared to extracts from HeLa or extracts from Tag-transformed XP variant fibroblasts. Complementation of XP-E extracts with XP-A, XP-D or XP-G extracts restored nucleotide excision activity to normal levels. XPET6/1 could prove a useful cell line for cloning of the XPE gene by functional complementation.
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PMID:Generation and characterization of an immortal cell line of xeroderma pigmentosum group E. 953 81

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

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

Recent studies have identified a link between the BRCA1 tumor suppressor and transcriptional regulation of a group of genes involved in nucleotide excision repair. There is some controversy regarding the precise mechanism of upregulation of XPE DDB2 or XPC by BRCA1, with some evidence suggesting that p53 is involved in their regulation. Some evidence suggests BRCA1 may stabilize p53 and direct regulation of DNA repair genes, although how BRCA1 stabilizes p53 remains unclear and whether BRCA1 can upregulate DNA repair genes in a p53-independent manner remains a possibility. A transcriptional component to the action of BRCA1 and involvement of XP genes brings up new and interesting questions about breast cancer development and therapy.
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PMID:Transactivation of repair genes by BRCA1. 1249 74

The most versatile cellular pathway for dealing with a large variety of structurally-unrelated DNA alterations is nucleotide excision repair (NER). Most genomic damage, if not repaired, may contribute to mutagenesis and carcinogenesis, as well as to cellular lethality. There are two subpathways of NER, termed global genomic repair (GGR) and transcription-coupled repair (TCR); While GGR deals with all repairable lesions throughout the genome, TCR is selective for the transcribed DNA strand in expressed genes. Proteins involved in the initial recognition of lesions for GGR as well as for TCR (i.e. RNA polymerase) may sometimes initiate gratuitous repair events in undamaged DNA. However, the damage recognition enzymes for GGR are normally maintained at very low levels unless the cells are genomically stressed. Following UV irradiation in human fibroblasts the efficiency of GGR is upregulated through activation of the p53 tumor suppressor gene. The transactivation role of p53 includes control of expression of the genes, XPC and XPE, which are implicated in GGR but not TCR. These inducible responses are essential for the efficient repair of the most prominent lesion produced by UV, the cyclobutane pyrimidine dimer (CPD). They are also clinically relevant, as we have shown them to operate upon chemical carcinogen DNA damage at levels to which humans are environmentally exposed (e.g. through smoking). Thus, for benzo(a)pyrene (at 10-50 adducts per 10(8) nucleotides) repair was essentially complete within 1 day in p53(+/+) human fibroblasts while no repair was detected within 3 days in p53(-/-) cells. The levels of all four DNA adducts formed by benzo(g)chrysene, also exhibited p53-dependent control in human fibroblasts. However, unlike humans most rodent tissues are deficient in the p53-dependent GGR pathway. Since rodents are used as surrogates for humans in environmental cancer risk assessment it is very important that we determine how they differ from humans with respect to DNA repair and oncogenic responses to environmental genotoxins.
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PMID:Functional characterization of global genomic DNA repair and its implications for cancer. 1464 13

Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) are genetic disorders with very different clinical features, but all associated with defects in nucleotide excision repair. Defects in the XPA or XPC genes confer sensitivity to UV carcinogenesis in both humans and mice, but only XPA(-/-) mice have increased acute responses to UV exposure, whereas XPC(-/-) mice are normal in this respect. Both XPE and XPF proteins have functions separate from their role in NER, but the exact nature of these functions has not yet been established. The CSA and CSB genes responsible for CS are both components of complexes associated with RNA polymerase II and their role is thought to be in assisting polII in dealing with transcription blocks. XPB and XPD proteins are components of transcription factor TFIIH, which is involved in both basal and activated transcription. XPB is part of the core of TFIIH and has a central role in transcription, whereas XPD connects the core to the CAK subcomplex, and can tolerate many different mutations. Subtle differences in the effects of these different mutations on the many activities of TFIIH and on its stability determine the clinical outcomes, which can be XP, TTD, XP with CS, XP with TTD or COFS. Features of single and double mutant mice indicate that the neurological and ageing features associated with these disorders result from the defects in NER in association with the transcriptional deficiencies. Skin tumours in XP patients have mutations characteristic of UV-induction in the ras, p53 and ptch genes, showing that sunlight-induced mutations in these genes are important in carcinogenesis in XP patients.
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PMID:DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. 1472 16

Immortalized cells frequently have disruptions of p53 activity and lack p53-dependent nucleotide excision repair (NER). We hypothesized that telomerase immortalization would not alter p53-mediated ultraviolet light (UV)-induced DNA damage responses. DNA repair proficient primary diploid human fibroblasts (GM00024) were immortalized by transduction with a telomerase expressing retrovirus. Empty retrovirus transduced cells senesced after a few doublings. Telomerase transduced GM00024 cells (tGM24) were cultured continuously for 6 months (>60 doublings). Colony forming ability after UV irradiation was dose-dependent between 0 and 20J/m2 UVC (LD50=5.6J/m2). p53 accumulation was UV dose- and time-dependent as was induction of p48(XPE/DDB2), p21(CIP1/WAF1), and phosphorylation on p53-S15. UV dose-dependent apoptosis was measured by nuclear condensation. UV exposure induced UV-damaged DNA binding as monitored by electrophoretic mobility shift assays using UV irradiated radiolabeled DNA probe was inhibited by p53-specific siRNA transfection. p53-Specific siRNA transfection also prevented UV induction of p48 and improved UV survival measured by colony forming ability. Strand-specific NER of cyclobutane pyrimidine dimers (CPD) within DHFR was identical in tGM24 and GM00024 cells. CPD removal from the transcribed strand was nearly complete in 6h and from the non-transcribed strand was 73% complete in 24h. UV-induced HPRT mutagenesis in tGM24 was indistinguishable from primary human fibroblasts. These wide-ranging findings indicate that the UV-induced DNA damage response remains intact in telomerase-immortalized cells. Furthermore, telomerase immortalization provides permanent cell lines for testing the immediate impact on NER and mutagenesis of selective genetic manipulation without propagation to establish mutant lines.
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PMID:Telomerase-immortalized human fibroblasts retain UV-induced mutagenesis and p53-mediated DNA damage responses. 1614 41

DNA repair defects can predispose to cancer development and progression. We previously showed that the breast and ovarian cancer susceptibility gene product BRCA1, through p53, upregulates expression of the XPE gene DDB2 encoding the nucleotide excision repair protein p 48. Both XPE and XPC are p53 target genes containing p53 response elements. To further explore the role of BRCA1 and p53 in repair of photoproducts, we eliminated wild type p53 from U2OS osteosarcoma cells and found that cyclobutane pyrimidine dimer (CPD) repair was markedly impaired following UV damage whereas repair of 6-4 photoproduct (6-4 PP) occurred efficiently. Overexpression of p53 in p53-null Calu-6 cells also enhanced CPD repair. In HCC1937 breast cancer cells, harboring mutant BRCA1 and p53 genes, repair of CPD was markedly impaired. Reintroduction of either p53 or BRCA1 using adenovirus vectors into HCC1937 alone had little effect on repair of CPD whereas the combination of p53 and BRCA1 resulted in efficient repair of CPD. Thus there appears to be a cooperative effect between p53 and BRCA1 that may involve induction of repair proteins, inhibition of p53-induced cell death by BRCA1 with altered p53 selectivity towards repair pathways and/or p53-independent effects of BRCA1 on CPD repair.
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PMID:Cooperation between BRCA1 and p53 in repair of cyclobutane pyrimidine dimers. 1635 11


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