Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clonogenic survival response to 254-nm ultraviolet light was measured in 2 strains of repair-proficient normal human fibroblasts and 4 strains of xeroderma pigmentosum (XP) fibroblasts belonging to complementation groups A, C, D and variant. In all strains except XPA, cells irradiated in plateau phase and subcultured immediately were much more resistant to the lethal effect of UV than cells irradiated in the exponential phase of growth. Typically, 10-20% of plateau-phase cells were extremely resistant. When the cultures were held in plateau phase for 24 h after irradiation and before subculture, there was a further enhance of survival. By use of a UV-specific endonuclease assay, no difference was found in the number of DNA lesions induced in exponentially growing and plateau cultures by the same dose of UV light. Thus plateau-phase cells appear to be more efficient in their DNA-repair capability than cells in exponential growth. XP group A cells were uniquely found to be deficient in the processes which lead to plateau-phase resistance. Since plateau-phase repair was not lacking in XP groups C, D and variant, it may be related to a DNA-repair process different from that which is responsible for the overall UV sensitivity of these cells.
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PMID:Resistance of plateau-phase human normal and xeroderma pigmentosum fibroblasts to the cytotoxic effect of ultraviolet light. 52 80

The UV hypersensitivity of xeroderma pigmentosum (XP) complementation group A cells is restored to near-normal by transfection of the XPA gene located on human chromosome 9. However, it has been reported that a cosmid related to a cDNA on chromosome 8 is also able to partially correct the UV sensitivity of XP-A cells. We describe here an investigation of a representative cosmid transfectant, denoted 2-0-A2. Whole cell extracts prepared from 2-0-A2 cells carried out DNA repair synthesis in vitro that was in the normal range, consistent with their UV-resistant phenotype. Immunoblotting indicated that 2-0-A2 cells expressed full-length XPA protein. This was unexpected because the 2-0-A2 cell line was thought to have been isolated by transfection of a cell line derived from patient XP2OS, and a known homozygous mutation in XP2OS prevents expression of XPA gene product. This mutation creates an AlwNI restriction endonuclease cleavage site in XPA and was not present in 2-0-A2. These results prompted an RFLP analysis which revealed that the 2-0-A2 cell line was not derived from XP2OS but from another line that fails to express XPA protein, XP12BE. It appears that the significant UV-resistance and DNA repair capacity of 2-0-A2 can be ascribed to the re-expression of XPA in XP12BE, and it is unnecessary to postulate a second XP-A complementing gene to explain the results.
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PMID:Analysis of cells harboring a putative DNA repair gene reveals a lack of evidence for a second independent xeroderma pigmentosum group A correcting gene. 751 40

The gene responsible for xeroderma pigmentosum (XP) group A has recently been cloned and designated XPA gene. Previous studies have shown that most Japanese XPA patients have homozygous mutations for the splicing site of intron 3 of the XPA gene, which was recognized by restriction endonuclease (RE) AlwNI (AlwNI mutation). Other mutations found to date have been the nonsense mutation at codon 228 in exon 6, recognized by RE HphI (HphI mutation), and at codon 116 in exon 3, recognized by RE MseI (MseI mutation). Using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis, we examined the point mutations of the XPA gene in 16 XPA patients, their parents, and their four asymptomatic siblings. We found that eight patients were homozygous for the AlwNI mutation, two were compound heterozygotes for the AlwNI mutation and the HphI mutation, one was a compound heterozygote for the AlwNI mutation and the MseI mutation, three were compound heterozygotes for the AlwNI mutation and an unidentified mutation, and two were compound heterozygotes for the HphI mutation and an unidentified mutation. Investigation of their clinical features suggested that the four patients who were heterozygous for the HphI mutation and the AlwNI or an unidentified mutation had milder clinical manifestations such as later development of skin cancers and milder neurological deterioration, than those patients who were either homozygous for the AlwNI mutation or heterozygous for the AlwNI mutation and MseI mutation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation of the clinical manifestations and gene mutations of Japanese xeroderma pigmentosum group A patients. 757 88

Human replication protein (RPA) functions in DNA replication, homologous recombination and nucleotide excision repair. This multisubunit single-stranded DNA-binding protein may be required to make unique protein-protein contacts because heterologous single-stranded binding proteins cannot substitute for RPA in these diverse DNA transactions. We report here that, by using affinity chromatography and immunoprecipitation, we found that human RPA bound specifically and directly to two excision repair proteins, the xeroderma pigmentosum damage-recognition protein XPA (refs 8, 9) and the endonuclease XPG (refs 10-13). Although it had been suggested that RPA might function before the DNA synthesis repair stage, our finding that a complex of RPA and XPA showed a striking cooperativity in binding to DNA lesions indicates that RPA may function at the very earliest stage of excision repair. In addition, by binding XPG, RPA may target this endonuclease to damaged DNA.
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PMID:RPA involvement in the damage-recognition and incision steps of nucleotide excision repair. 770 Mar 86

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 human XPF-ERCC1 protein complex is one of several factors known to be required for general nucleotide excision repair. Genetic data indicate that both proteins of this complex are necessary for the repair of interstrand cross-links, perhaps via recombination. To determine whether XPF-ERCC1 completes a set of six proteins that are sufficient to carry out excision repair, the human XPF and ERCC1 cDNAs were coexpressed in Sf21 insect cells from a baculovirus vector. The purified complex contained the anticipated 5' junction-specific endonuclease activity that is stimulated through a direct interaction between XPF and replication protein A (RPA). The recombinant complex also complemented extracts of XP-F cells and Chinese hamster ovary mutants assigned to complementation groups 1, 4, and 11. Furthermore, reconstitution of the human excision nuclease was observed with a mixture of five repair factors (XPA, XPC, XPG, TFIIH, and RPA) and the recombinant XPF-ERCC1, thus verifying that no additional protein factors are needed for the specific dual incisions characteristic of human excision repair.
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PMID:Reconstitution of human excision nuclease with recombinant XPF-ERCC1 complex. 901 42

Genetic information is frequently disturbed by introduction of modified or mismatch bases into duplex DNA, and hence all organisms contain DNA repair systems to restore normal genetic information by removing such damaged bases or nucleotides and replacing them by correct ones. The understanding of this repair mechanism is a central subject in cell biology. This review focuses on the three-dimensional structural views of damaged DNA recognition by three proteins. The first protein is T4 endonuclease V (T4 endo V), which catalyzes the first reaction step of the excision repair pathway to remove pyrimidine-dimers (PD) produced within duplex DNA by UV irradiation. The crystal structure of this enzyme complexed with DNA containing a thymidine-dimer provided the first direct view of DNA lesion recognition by a repair enzyme, indicating that the DNA kink coupled with base flipping-out is important for damaged DNA recognition. The second is very short patch repair (Vsr) endonuclease, which recognizes a TG mismatch within the five base pair consensus sequence. The crystal structure of this enzyme in complex with duplex DNA containing a TG mismatch revealed a novel mismatch base pair recognition scheme, where three aromatic residues intercalate from the major groove into the DNA to strikingly deform the base pair stacking but the base flipping-out does not occur. The third is human nucleotide excision repair (NER) factor XPA, which is a major component of a large protein complex. This protein has been shown to bind preferentially to UV- or chemical carcinogen-damaged DNA. The solution structure of the XPA central domain, essential for the interaction of damaged DNA, was determined by NMR. This domain was found to be divided mainly into a (Cys)4-type zinc-finger motif subdomain for replication protein A (RPA) recognition and the carboxyl terminal subdomain responsible for DNA binding.
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PMID:Three-dimensional structural views of damaged-DNA recognition: T4 endonuclease V, E. coli Vsr protein, and human nucleotide excision repair factor XPA. 1094 33

Defects in nucleotide excision repair (NER) as defined by the UV sensitivity of xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) patients has lead to the identification of most of the genes involved: XPA through XPG, CSA and CSB. Whereas XP patients often show an increased risk for skin cancer after exposure to sunlight, this is not the case for patients with CS and TTD. Several CS patients have been shown to carry a defect in the XPG gene. The XPG, a structure specific endonuclease makes the incision 3' of damage and is also involved in the subsequent 5'incision during the NER process. In addition, XPG plays a role in the removal of oxidative DNA damage. The Drosophila XPG gene was isolated and based on the molecular defect of a spontaneous (insertion) and an EMS induced mutant, it was shown that a mutated XPG is responsible for the Drosophila mutagen-sensitive mutants mus201. One of these mutants, mus201(D1) has been used extensively in studies of the effects and mechanisms of many chemical mutagens as well as X-rays. The results of these studies are discussed in the light of the finding that mus201p is the Drosophila homologue of XPG.
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PMID:Induced mutagenic effects in the nucleotide excision repair deficient Drosophila mutant mus201(D1), expressing a truncated XPG protein. 1110 4

The multisubunit basal transcription factor IIH (TFIIH) has a dual involvement in nucleotide excision repair (NER) of a variety of DNA lesions, including UV-induced photoproducts, and RNA polymerase II transcription. In both processes, TFIIH is implicated with local DNA unwinding, which is attributed to its helicase subunits XPB and XPD. To further define the role of TFIIH in NER, functional interactions between TFIIH and other DNA repair proteins were analyzed. We show that the TFIIH-associated ATPase activity is stimulated by both XPA and the XPC-HR23B complex. However, while XPA promotes the ATPase activity specifically in the presence of damaged DNA, stimulation by XPC-HR23B is lesion independent. Furthermore, we reveal that TFIIH inhibits the structure-specific endonuclease activities of both XPG and ERCC1-XPF, responsible for the 3' and 5' incision in NER, respectively. The inhibition occurs in the absence of ATP and is reversed upon addition of ATP. These results point toward additional roles for TFIIH and ATP during NER distinct from a requirement for DNA unwinding in the regulation of the endonuclease activities of XPG and ERCC1-XPF.
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PMID:Novel functional interactions between nucleotide excision DNA repair proteins influencing the enzymatic activities of TFIIH, XPG, and ERCC1-XPF. 1114 Oct 66

Here, we describe the assembly of the nucleotide excision repair (NER) complex in normal and repair-deficient (xeroderma pigmentosum) human cells, employing a novel technique of local UV irradiation combined with fluorescent antibody labeling. The damage recognition complex XPC-hHR23B appears to be essential for the recruitment of all subsequent NER factors in the preincision complex, including transcription repair factor TFIIH. XPA associates relatively late, is required for anchoring of ERCC1-XPF, and may be essential for activation of the endonuclease activity of XPG. These findings identify XPC as the earliest known NER factor in the reaction mechanism, give insight into the order of subsequent NER components, provide evidence for a dual role of XPA, and support a concept of sequential assembly of repair proteins at the site of the damage rather than a preassembled repairosome.
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PMID:Sequential assembly of the nucleotide excision repair factors in vivo. 1151 74


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