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)

TFIIH is a multiprotein complex that plays a central role in both transcription and DNA repair. The subunit p62 is a structural component of the TFIIH core that is known to interact with VP16, p53, Eralpha, and E2F1 in the context of activated transcription, as well as with the endonuclease XPG in DNA repair. We used limited proteolysis experiments coupled to mass spectrometry to define structural domains within the conserved N-terminal part of the molecule. The first domain identified resulted from spontaneous proteolysis and corresponds to residues 1-108. The second domain encompasses residues 186-240, and biophysical characterization by fluorescence studies and NMR analysis indicated that it is at least partially folded and thus may correspond to a structural entity. This module contains a region of high sequence conservation with an invariant FWxxPhiPhi motif (Phi representing either tyrosine or phenylalanine), which was also found in other protein families and could play a key role as a protein-protein recognition module within TFIIH. The approach used in this study is general and can be straightforwardly applied to other multidomain proteins and/or multiprotein assemblies.
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PMID:Domain architecture of the p62 subunit from the human transcription/repair factor TFIIH deduced by limited proteolysis and mass spectrometry analysis. 1553 47

Inhibitory member of the ASPP family (iASPP) is an evolutionarily conserved inhibitor of p53, and its expression is upregulated in human breast carcinomas expressing wild-type p53. To examine the role of iASPP in acute leukemia (AL), we analyzed iASPP mRNA expression in AL by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). PCR products were confirmed by restriction endonuclease BstX I digestion and sequencing analysis. The results showed that median levels of iASPP gene expression in cells of AL were significantly higher than those in cells from normal donors and AL patients in complete remission (CR) (P = 0.019, 0.021, respectively). There was no significant difference between acute lymphocytic leukemia (ALL) cells and acute myeloid leukemia (AML) cells (P = 0.593). The expression level of iASPP gene and its overexpression in M3 and M4EO were significantly lower than in other subtypes of AML. However, iASPP gene expression in AL cells was not associated with gender, age, initial white blood cell count or p53 type, but was associated with CD34 expression. The results of the present study suggest that iASPP gene overexpression may play an important role in the leukemogenesis and/or disease progression of AL.
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PMID:The expression of iASPP in acute leukemias. 1560 67

Nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSBs) entails two principal mechanisms: modification of DNA ends prior to ligation (error-prone rejoining) or precise ligation without modification if the DNA ends are complementary (error-free repair). Error-prone rejoining is mutagenic, because it can lead to destruction of coding sequence or to chromosomal aberrations, and therefore must be tightly regulated. Previous studies on the role of the p53 tumor suppressor in the regulation of NHEJ have yielded conflicting results, but a rigorous analysis of NHEJ proficiency and fidelity in a purely chromosomal context has not been carried out. To this end, we created novel repair plasmid substrates that integrate into the genome. DSBs generated by the I-SceI endonuclease within these substrates were repaired by either error-prone rejoining or precise ligation. We found that the expression of wild-type p53 inhibited any repair-associated DNA sequence deletion, including a more than 250-fold inhibition of error-prone rejoining events compared to p53-null cells, while any promoting effect of p53 on precise ligation could not be directly evaluated. The role of p53 in NHEJ appeared to involve a direct transactivation-independent mechanism, possibly restricting DNA end-modification by blocking the annealing of single strands along flanking stretches of microhomology. The inhibition of error-prone rejoining by p53 did not apply to the rejoining of DSBs induced by ionizing radiation. In conclusion, our data suggest that p53 restricts the mutagenic effects of NHEJ without compromising repair proficiency or cell survival, thereby maintaining genomic stability.
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PMID:Nonhomologous end-joining of site-specific but not of radiation-induced DNA double-strand breaks is reduced in the presence of wild-type p53. 1568 24

The p53 protein is redox-sensitive in vitro but in vivo effectors of this sensitivity are not known. In yeasts deficient for thioredoxin (Trx) reductase (TRR), p53 accumulates in an inactive, oxidized form, suggesting a role for TRR-Trx in controlling p53. In mammalian cells, p53 binds to redox factor-1 (APE/Ref-1), an enzyme containing an abasic endonuclease domain involved in base excision repair, and a thiol reductase domain recycled by Trx and involved in regulating the transcription factor AP-1. To evaluate the role of TRR and APE/Ref-1 in p53 regulation, we have abrogated their expression using RNA interference in cell lines expressing wild-type p53. Inhibition of TRR resulted in accumulation of oxidized Trx and increased levels and DNA-binding activity of p53, with no phosphorylation of Ser15 or Ser20. In contrast, inhibition of APE/Ref-1 accelerated p53 protein turnover, resulting in a decrease in p53 levels and activity. However, inhibition of either TRR or APE/Ref-1 did not prevent activation and accumulation of p53 in response to DNA-damage by doxorubicin. When both factors were inhibited, basal levels of p53 were restored. These results suggest that TRR-Trx and APE/Ref-1 cooperate in the control of basal p53 activity, but not in its induction by DNA-damage.
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PMID:Roles of thioredoxin reductase 1 and APE/Ref-1 in the control of basal p53 stability and activity. 1582 42

The development of ischemic tolerance in the brain, whereby a brief period of sublethal 'preconditioning' ischemia attenuates injury from subsequent severe ischemia, may involve the activation of multiple intracellular signaling events that promote neuronal survival. In this study, the potential role of inducible DNA base-excision repair (BER), an endogenous adaptive response that prevents the detrimental effect of oxidative DNA damage, has been studied in the rat model of ischemic tolerance produced by three episodes of ischemic preconditioning (IP). This paradigm of IP, when applied 2 and 5 days before 2-h middle cerebral artery occlusion (MCAO), significantly decreased infarct volume in the frontal-parietal cortex 72 h later. Correlated with this protective effect, IP markedly attenuated the nuclear accumulations of several oxidative DNA lesions, including 8-oxodG, AP sites, and DNA strand breaks, after 2-h MCAO. Consequently, harmful DNA damage-responsive events, including NAD depletion and p53 activation, were reduced during postischemic reperfusion in preconditioned brains. The mechanism underlying the decreased DNA damage in preconditioned brain was then investigated by measuring BER activities in nuclear extracts. Beta-polymerase-mediated BER activity was markedly increased after IP, and this activation occurred before (24 h) and during the course of ischemic tolerance (48 to 72 h). In similar patterns, the activities for AP site and 8-oxodG incisions were also upregulated after IP. The upregulation of BER activities after IP was likely because of increased expression of repair enzymes beta-polymerase, AP endonuclease, and OGG1. These results suggest that the activation of the BER pathway may contribute to IP-induced neuroprotection by enhancing the repair of endogenous oxidative DNA damage after ischemic injury.
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PMID:Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. 1600 Oct 17

The Mus81-Eme1 endonuclease is implicated in the efficient rescue of broken replication forks in Saccharomyces cerevisiae and Schizosaccharomyces pombe. We have used gene targeting to study the function of the Mus81-Eme1 endonuclease in mammalian cells. Mus81-deficient mice develop normally and are fertile. Surprisingly, embryonic fibroblasts from Mus81(-/-) animals fail to proliferate in vitro. This proliferation defect can be rescued by expression of the papillomavirus E6 protein that promotes degradation of p53. When grown in culture, Mus81(-/-) cells have elevated levels of DNA damage, acquire chromosomal aberrations, and are hypersensitive to agents that generate DNA cross-links. In contrast to the situation in yeast, murine Mus81 is not required for replication restart following camptothecin treatment. Mus81(-/-) mice and cells are hypersensitive to DNA cross-linking agents. Cross-link-induced double-strand break formation is normal in Mus81(-/-) cells, but the resolution of repair intermediates is not. The persistence of Rad51 foci in Mus81(-/-) cells suggests that Mus81 acts at a late step in the repair of cross-link-induced lesions. Despite these defects, Mus81(-/-) mice do not show increased predisposition to lymphoma or any other malignancy in the first year of life.
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PMID:Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis. 1610 4

The severe xeroderma pigmentosum/Cockayne syndrome (XP/CS) syndrome is caused by mutations in the XPB, XPD and XPG genes that encode the helicase subunits of TFIIH and the 3' endonuclease of nucleotide excision repair (NER). Because XPB and XPD have been implicated in p53-mediated apoptosis, we examined the possible involvement of XPG in this process. After ultraviolet light (UV) irradiation, primary fibroblasts of XP complementation group G (XP-G) individuals with CS enter apoptosis more readily than other NER-deficient cells, but this is unlinked to unrepaired damage. These XP-G/CS cells accumulate p53 post-UV but they fail to accumulate the 90/92 kDa isoforms of Mdm2 and their cellular distribution of Mdm2 is impaired. Apoptosis levels revert to wild type, Mdm2 90/92 kDa isoforms accumulate, and Mdm2 regains its normal post-UV nuclear location in transduced XP-G/CS cells expressing wild-type XPG, but not an XPG catalytic site mutant. These results suggest that XPG suppresses UV-induced apoptosis and that this suppression, most simply, requires its endonuclease function.
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PMID:Suppression of UV-induced apoptosis by the human DNA repair protein XPG. 1616 68

Chronic arsenic exposure is known to produce arsenicosis and cancer. To ascertain whether perturbation of methylation plays a role in such carcinogenesis, the degree of methylation of p53 and p16 gene in DNA obtained from blood samples of people chronically exposed to arsenic and skin cancer subjects was studied. Methylation-specific restriction endonuclease digestion followed by polymerase chain reaction (PCR) of gene p53 and bisulfite treatment followed by methylation-sensitive PCR of gene p16 have been carried out to analyze the methylation status of the samples studied. Significant DNA hypermethylation of promoter region of p53 gene was observed in DNA of arsenic-exposed people compared to control subjects. This hypermethylation showed a dose-response relationship. Further, hypermethylation of p53 gene was also observed in arsenic-induced skin cancer patients compared to subjects having skin cancer unrelated to arsenic, though not at significant level. However, a small subgroup of cases showed hypomethylation with high arsenic exposure. Significant hypermethylation of gene p16 was also observed in cases of arsenicosis exposed to high level of arsenic. In man, arsenic has the ability to alter DNA methylation patterns in gene p53 and p16, which are important in carcinogenesis.
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PMID:DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy. 1625 83

Status epilepticus (SE)-induced neuronal death is morphologically necrotic and is initiated by excessive glutamate release, which activates postsynaptic N-methyl-D-aspartate (NMDA) receptors and triggers receptor-mediated calcium influx (excitotoxicity). This results in activation of intracellular proteases and neuronal nitric oxide synthase, with generation of free radicals, and damage to cellular membranes, structural proteins, and essential enzymes. Programmed cell death mechanisms, such as p53 activation, activation of cell death-promoting Bcl-2 family members, and endonuclease-induced DNA laddering, occur in SE-induced neuronal death. Caspase-independent excitotoxic mechanisms, such as NMDA-induced calpain I activation, with activation and translocation of the cell death-promoting Bcl-2 family member Bid from cytoplasm to mitochondria, and subsequent translocation of apoptosis-inducing factor and endonuclease G to nuclei (which cause large-scale and internucleosomal DNA cleavage, respectively), may be triggered by SE. Poly(ADP-ribose) polymerase-1 (PARP-1) activation and cysteinyl cathepsin and DNase II release from lysosomes may occur following SE as well, but these events await future investigation. In the future, rational combinations of central nervous system-penetrable neuroprotective agents, based on our knowledge of excitotoxic mechanisms, may be useful in refractory human SE.
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PMID:Prolonged seizures and cellular injury: understanding the connection. 1627 99

Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR beta gene enhancer (E beta) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the E beta mutation into p53-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.
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PMID:Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations. 1647 78


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