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)

The XPA gene was initially cloned based on the ability of its cDNA to improve survival of cells from xeroderma pigmentosum complementation group A (XP-A) patients following irradiation of the cells with UV. We used plasmid host cell reactivation assays to compare UV mutagenesis and the proficiency of DNA repair in a cell line from an XP-A patient, XP2OS(SV40), two derivative cell lines stably expressing XPA cDNAs and in a DNA repair proficient human cell line. Expression of XPA protein in XP2OS cells allowed them to repair UV-treated plasmid pRSVCAT, increasing activity of the damaged CAT marker gene > 100-fold to levels produced by similarly damaged plasmids in normal cells. Expression of the XPA protein in XP2OS cells improved replication of the UV-treated shuttle vector pSP189, increasing plasmid survival and decreasing plasmid mutation frequency to the levels measured in normal cells. The sequence locations of most mutation hotspots in the plasmid marker gene were similar for the three cell lines and the differences did not correlate with the DNA repair status of the cells. This suggests that the location of mutation hotspots is not directly influenced by DNA repair. Expression of the XPA protein did cause a shift in the types of mutations seen in the plasmid gene. In the XP2OS cells > 95% of the plasmid mutations were G:C-->A:T transition mutations. In contrast, XP2OS cells expressing XPA produced other types of mutations: three times as many transversion mutations and a 12-fold increase in mutations at A:T base pairs. Furthermore, the distribution of these types of mutations was similar to the proportions measured in normal cells. Strikingly similar patterns of transition and transversion mutations were found by examination of reports of XP and non-XP skin carcinomas containing mutations in the p53 tumor suppressor gene, suggesting that the repair status of the cells influenced mutagenesis associated with these skin cancers. Our data suggest that loss of XPA gene function may be sufficient to effect the quantitative and qualitative changes in mutagenesis associated with the large increase in skin cancers seen in XP-A patients.
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PMID:Expression of a transfected DNA repair gene (XPA) in xeroderma pigmentosum group A cells restores normal DNA repair and mutagenesis of UV-treated plasmids. 761 89

A great deal of the energy and time of a cell is invested in DNA repair activities. The first step in DNA repair pathways is recognition of the lesion on the DNA. The classical lesion-recognizing proteins interact with other repair proteins to form multiprotein complexes most notable of which are those that function in Nucleotide Excision Repair (NER). Proteins involved in lesion recognition include HMG1 and 2 recognizing cisplatin adducts but also maintaining active nucleosome structures and interacting with loops in cruciforms; HMG-box nuclear proteins; XPA and XPC lacking in xeroderma pigmentosum patients and involved in lesion recognition during NER; p53 recognizing strand breaks and insertion/deletion mismatches and causing arrest in the cell cycle; MSH2 mismatch repair protein identified as the human colon cancer gene product; and others including the transcription factor YB-1 that binds to depurinated DNA with a higher affinity compared with undamaged DNA. Other type of lesion-recognizing proteins are also repair enzymes like the O(6)-methylguanine-DNA methyltransferase and DNA glycosylases. Lesion recognition is an important process and might be the rate-limiting step in the overall repair process.
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PMID:DNA lesion-recognizing proteins and the p53 connection. 861 13

The molecular pathway of p53-dependent apoptosis (programmed cell death) is poorly understood. Because p53 binds to the basal transcription-repair complex TFIIH and modulates its DNA helicase activities, we hypothesized that TFIIH DNA helicases XPB and XPD are members of the p53-mediated apoptotic pathway. Whereas transfer of a wild-type p53 expression vector by microinjection or retroviral infection into primary normal human fibroblasts resulted in apoptosis, primary fibroblasts from individuals with xeroderma pigmentosum (XP), who are deficient in DNA repair and have germ-line mutations in the XPB or XPD gene, but not in the XPA or XPC gene, have a deficiency in the apoptotic response. This deficiency can be rescued by transferring the wild-type XPB or XPD gene into the corresponding mutant cells. XP-D lymphocytes also have a decreased apoptotic response to DNA damage by adriamycin, indicating a physiologically relevant deficiency. The XP-B or XP-D mutant cells undergo a normal apoptotic response when microinjected with the Ich-L, and ICE genes. Analyses of p53 mutants and the effects of microinjected anti-p53 antibody, Pab421, indicate that the carboxyl terminus of p53 may be required for apoptosis. Direct microinjection of the p53 carboxy-terminal-derived peptide (amino acid residues 319-393) resulted in apoptosis of primary normal human fibroblasts. These results disclose a novel pathway of p53-induced apoptosis.
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PMID:The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. 867 9

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 rapid accumulation of the p53 gene product is considered to be an important component of the cellular response to a variety of genotoxins. In order to gain insights on the biochemical pathways leading to p53 stabilization, the effect of (+/-) 7,8-dihydroxy-anti-9, 10-epoxy-7,8,9,10-tetrahydrobenzo(a)-pyrene [(+/-)-anti-BPDE] induced DNA damage on p53 protein levels was investigated in various repair-proficient and repair-deficient human cells. Brief exposure of normal human fibroblasts to 0.05-1 microM (+/-)-anti-BPDE resulted in elevated p53 protein levels as compared to the constitutive levels of control cells. The rapid induction response, detectable within a few hours, was sustained up to a period of at least 24 h. Repair-proficient and repair-deficient (XPA) human lymphoblastoid cells showed a similar response. The poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide (3-AB), diminished the p53 induction response by concomitantly decreasing the extent of (+/-)-anti-BPDE induced DNA damage in cells pretreated with the inhibitor. However, the direct involvement of poly ADP-ribosylation was also apparent as 3-AB was able to attenuate (approximately 50%) the p53 response by post-damage inhibitor treatment of the cells. Inhibition of cellular DNA replication by hydroxyurea and AraC, in the presence or absence of DNA damage, also resulted in rapid p53 accumulation in repair-deficient cells. On the contrary, inhibition of protein kinase C (PKC) by calphostin-C led to an abrogation of (+/-)-anti-BPDE mediated p53 induction. Analysis of the downstream effects of carcinogen treatment showed that the lymphoblastoid cells undergo DNA fragmentation indicative of apoptosis while fibroblasts exhibit cell cycle arrest at the G1-S boundary.
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PMID:Modulation of (+/-)-anti-BPDE mediated p53 accumulation by inhibitors of protein kinase C and poly(ADP-ribose) polymerase. 904 87

It is generally presumed that xeroderma pigmentosum (XP) patients are extremely sensitive to developing UV erythema, and that they have a more than 1000-fold increased skin cancer risk. Recently established mouse models for XP can be employed to investigate the mechanism of these increased susceptibilities. In line with human data, both XPA and XPC knockout mice have been shown to have an increased susceptibility to UVB induced squamous cell carcinomas. In XPA knockouts, nucleotide excision repair of UV induced DNA photolesions is completely defective (i.e., both global genome repair and transcription coupled repair are defective). We determined the strand specific removal of cyclobutane pyrimidine dimers and pyrimidine [6-4] pyrimidone photoproducts from the p53 gene in cells from XPC knockout mice and wild-type littermates. Analogous to human XPC cells, embryonic fibroblasts from XPC knockout mice are only capable of performing transcription coupled repair of DNA photolesions. We show that these XPC knockout mice, in striking contrast to XPA knockout mice, do not have a lower minimal erythema/edema dose than their wild-type littermates. Hence, defective global genome repair appears to lead to skin cancer susceptibility, but does not influence the sensitivity to acute effects of UVB radiation, such as erythema and edema. The latter phenomena thus relate to the capacity to perform transcription coupled repair, which suggests that blockage of RNA synthesis is a key event in the development of UV erythema and edema.
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PMID:Defective global genome repair in XPC mice is associated with skin cancer susceptibility but not with sensitivity to UVB induced erythema and edema. 954 Sep 83

Xeroderma pigmentosum (XP) patients with a defect in the nucleotide excision repair gene XPA, develop tumors with a high frequency on sun-exposed areas of the skin. Here we describe that hairless XPA-deficient mice also develop skin tumors with a short latency time and a 100% prevalence after daily exposure to low doses of U.V.B. Surprisingly and in contrast to U.V.B.-exposed repair proficient hairless mice who mainly develop squamous cell carcinomas, the XPA-deficient mice developed papillomas with a high frequency (31%) at a U.V. dose of 32 J/m2 daily. At the highest daily dose of 80 J/m2 mainly squamous cell carcinomas (56%) and only 10% of papillomas were found in XPA-deficient hairless mice. p53 gene mutations were examined in exons 5, 7 and 8 and were detected in only 3 out of 37 of these skin tumors, whereas in tumors of control U.V.B.-irradiated wild type littermates this frequency was higher (45%) and more in line with our previous data. Strikingly, a high incidence of activating ras gene mutations were observed in U.V.B.-induced papillomas (in 11 out of 14 tumors analysed). In only two out of 14 squamous cell carcinomas we found similar ras gene mutations. The observed shift from squamous cell carcinomas in wild type hairless mice to papillomas in XPA-deficient hairless mice, and a corresponding shift in mutated cancer genes in these tumors, provide new clues on the pathogenesis of chemically- versus U.V.B.-induced skin carcinogenesis.
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PMID:XPA-deficiency in hairless mice causes a shift in skin tumor types and mutational target genes after exposure to low doses of U.V.B. 961 29

The protein proliferating cell nuclear antigen (PCNA) is an auxiliary factor for DNA polymerase delta and is involved in the resynthesis step of nucleotide excision repair (NER). After UV irradiation of quiescent cells, PCNA forms an insoluble complex with nuclear substructures. We have investigated associations between NER and its subcomponent pathway, transcription coupled repair (TCR) on PCNA complex formation using genetically related hamster cell lines with different repair characteristics. In DNA repair proficient cells, the PCNA complex was readily detectable within 30 min after UV irradiation by both immunofluorescence and western blot analyses. This complex formation after UV occurs efficiently in quiescent cells. In UV5 (human XP-D homolog) and UV 24 (human XP-B homolog) cells, which are totally deficient in NER, the PCNA complex was not detectable at 30 min after UV. The PCNA complex formation is restored to normal levels in UV5 cells after transfection with the human XPD gene, encoding a subunit of the basal transcription factor, TFIIH. In UV61 (Human CS-B homolog) cells, that are defective only in transcription coupled repair (TCR) of cyclobutane pyrimidine dimers (CPDs), the rate of PCNA complex formation was 2-fold slower than in repair proficient cells. This defect was complemented by transfection of the CSB gene into the UV61 cells. We thus conclude that efficient PCNA complex formation after UV is dependent upon both the NER and TCR pathways in hamster cells. The association of several other DNA repair proteins including XPA, RPA, TFIIH and p53 with the insoluble PCNA complex in UV treated cells suggests a central role for PCNA in different steps of NER.
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PMID:Efficient PCNA complex formation is dependent upon both transcription coupled repair and genome overall repair. 987 89

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

The small DNA fragment thymidine dinucleotide (pTpT) stimulates photoprotective responses in mammalian cells and intact skin. These responses include increased melanogenesis (tanning) and enhanced repair of DNA damage induced by ultraviolet (UV) light. Here we show that pTpT treatment of human keratinocytes enhances their repair of DNA damaged by the chemical carcinogen benzo(a)pyrene (BP), as determined by increased expression of a transfected BP-damaged reporter plasmid containing the chloramphenicol acetyltransferase (CAT) gene. The pTpT-enhanced repair of this BP-damaged plasmid is accomplished at least in part through activation of the p53 tumor suppressor protein and transcription factor, because p53-null H1299 cells showed enhanced repair only if previously transfected with a p53-expression vector. To elucidate the mechanism of this enhanced DNA repair, we examined the expression of p21 and proliferating cell nuclear antigen (PCNA), proteins known to be regulated by p53, as well as the XPA protein, which is mutated in the inherited repair-deficient disorder xeroderma pigmentosum (XP) group A and is necessary for the recognition of UV-induced DNA photoproducts. The p53, PCNA and XPA proteins were all up-regulated within 48 h after the addition of pTpT. Taken together, these data demonstrate that pTpT-enhanced repair of DNA damaged by either UV irradiation or chemical mutagens can be achieved in human cells by exposure to small DNA fragments at least in part through the activation of p53 and increased expression of p53-regulated genes.
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PMID:Enhanced repair of benzo(a)pyrene-induced DNA damage in human cells treated with thymidine dinucleotides. 1010 40


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