Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that two Chinese hamster mutants deficient in the RAD51 paralogs XRCC2 and XRCC3 show reduced radiosensitization after treatment with caffeine, thus implicating homology-directed repair (HDR) of DNA double-strand breaks (DSBs) in the mechanism of caffeine radiosensitization. Here, we investigate directly the effect of caffeine on HDR initiated by DSBs induced by a rare cutting endonuclease (I-SceI) into one of two direct DNA repeats. The results demonstrate a strong inhibition by caffeine of HDR in wild-type cells, and a substantial reduction of this effect in HDR-deficient XRCC3 mutant cells. Inhibition of HDR and cell radiosensitization to killing shows similar dependence on caffeine concentration suggesting a cause-effect relationship between these effects. UCN-01, a kinase inhibitor that effectively abrogates checkpoint activation in irradiated cells, has only a small effect on HDR, indicating that similar to radiosensitization, inhibition of checkpoint signaling is not sufficient for HDR inhibition. Recombination events occurring during treatment with caffeine are characterized by rearrangements reminiscent to those previously reported for the XRCC3 mutant, and immunofluorescence microscopy demonstrates significantly reduced formation of IR-specific RAD51 foci after caffeine treatment. In summary, our results identify inhibition of HDR as a significant contributor to caffeine radiosensitization.
 ...
PMID:Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks. 1473 17

The aims of this study were to investigate mechanisms of action involved in H2AX phosphorylation by DNA interstrand crosslinking (ICL) agents and determine whether gammaH2AX could be a suitable pharmacological marker for identifying potential ICL cellular chemosensitivity. In normal human fibroblasts, after treatment with nitrogen mustard (HN2) or cisplatin, the peak gammaH2AX response was detected 2-3 h after the peak of DNA ICLs measured using the comet assay, a validated method for detecting ICLs in vitro or in clinical samples. Detection of gammaH2AX foci by immunofluorescence microscopy could be routinely detected with 6-10 times lower concentrations of both drugs compared to detection of ICLs using the comet assay. A major pathway for repairing DNA ICLs is the initial unhooking of the ICL by the ERCC1-XPF endonuclease followed by homologous recombination. HN2 or cisplatin-induced gammaH2AX foci persisted significantly longer in both, ERCC1 or XRCC3 (homologous recombination) defective Chinese hamster cells that are highly sensitive to cell killing by ICL agents compared to wild type or ionising radiation sensitive XRCC5 cells. An advantage of using gammaH2AX immunofluorescence over the comet assay is that it appears to detect ICL chemosensitivity in both ERCC1 and HR defective cells. With HN2 and cisplatin, gammaH2AX foci also persisted in chemosensitive human ovarian cancer cells (A2780) compared to chemoresistant (A2780cisR) cells. These results show that gammaH2AX can act as a highly sensitive and general marker of DNA damage induced by HN2 or cisplatin and shows promise for predicting potential cellular chemosensitivity to ICL agents.
 ...
PMID:Histone H2AX phosphorylation as a molecular pharmacological marker for DNA interstrand crosslink cancer chemotherapy. 1850 35

In recent years, multiple factors involved in DNA double-strand break (DSB) repair have been characterised in Arabidopsis thaliana. Using homologous sequences in somatic cells, DSBs are mainly repaired by two different pathways: synthesis-dependent strand annealing (SDSA) and single-strand annealing (SSA). By applying recombination substrates in which recombination is initiated by the induction of a site-specific DSB by the homing endonuclease I-SceI, we were able to characterise the involvement of different factors in both pathways. The nucleases MRE11 and COM1, both involved in DSB end processing, were not required for either SDSA or SSA in our assay system. Both SDSA and SSA were even more efficient without MRE11, in accordance with the fact that a loss of MRE11 might negatively affect the efficiency of non-homologous end joining. Loss of the classical recombinase RAD51 or its two paralogues RAD51C and XRCC3, as well as the SWI2/SNF2 remodelling factor RAD54, resulted in a drastic deficiency in SDSA but had hardly any influence on SSA, confirming that a strand exchange reaction is only required for SDSA. The helicase FANCM, which is postulated to be involved in the stabilisation of recombination intermediates, is surprisingly not only needed for SDSA but to a lesser extent also for SSA. Both SSA and SDSA were affected only weakly when the SMC6B protein, implicated in sister chromatid recombination, was absent, indicating that SSA and SDSA are in most cases intrachromatid recombination reactions.
 ...
PMID:The requirement for recombination factors differs considerably between different pathways of homologous double-strand break repair in somatic plant cells. 2286 Jun 89

A subset of human tumors ensures indefinite telomere length maintenance by activating a telomerase-independent mechanism known as Alternative Lengthening of Telomeres (ALT). Most tumor cells of ALT origin share a constellation of unique characteristics, which include large stores of extra-chromosomal telomeric material, chronic telomere dysfunction and a peculiar enrichment in chromosome ends with 5' C-rich overhangs. Here we demonstrate that acute telomere de-protection and the subsequent DNA damage signal are not sufficient to facilitate formation of 5' C-overhangs at the chromosome end. Rather chromosome ends bearing 5' C-overhangs are a by-product of rapid cleavage events, processing of which occurs independently of the DNA damage response and is partly mediated through the XRCC3 endonuclease.
 ...
PMID:5' C-rich telomeric overhangs are an outcome of rapid telomere truncation events. 2334 16

Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of atherosclerosis. Genetic research on coronary artery disease (CAD) has traditionally focused on investigation aimed at identifying disease-susceptibility genes. The aim of this study was to investigate the relationship between AP-endonuclease-1 (Asp148Glu), XRCC1 (Arg399Gln), XRCC3 (Thr241Met), XPD (Lys751Gln), XPG (Asp1104His), and hOGG1 (Ser326Cys), gene polymorphisms and the risk of developing CAD in a Turkish population. The study population consisted of 197 patients with acute coronary syndrome (ACS) with chronic CAD and 135 healthy subjects' age and sex matched. Gene polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism method. We demonstrated for the first time, a positive association of XRCC3 and hOGG1 DNA repair gene variants with CAD risk. XRCC3 Thr/Thr genotype and Thr allele frequencies were significantly increased in ACS and chronic CAD patients compared with the control group (p<0.05). It was also observed that there is a protective role of XRCC3 Met alleles against both ACS and chronic CAD (p<0.05). hOGG1 Cys alleles were found significantly higher in ACS patients than in the control group and carriers of the Cys allele had a 1.7-fold increased risk for ACS. In addition, we confirmed the association of XRCC3 Thr241Met and hOGG1 Ser326Cys gene variants with CAD by haplotype analysis. We found that CAD risk is associated with XRCC3 Thr: hOGG1 Cys haplotype, whereas XRCC3 Met: hOGG1 Ser haplotype was found to be protective against the disease. The preliminary results suggested that XRCC3 and hOGG1 genetic variants may be risk factors by affecting the enzyme's function that may lead to development of CAD.
 ...
PMID:Association between genetic variants of DNA repair genes and coronary artery disease. 2336 30

One of the main effects of various stress factors, including ionizing radiation, is DNA damage. Accumulation of DNA damage and somatic mutations in the somatic tissues is regarded as one of the basic mechanisms of aging. We have developed an approach to the study of molecular and genetic mechanisms of radioadaptation, which is based on the analysis of changes in the lifespan of Drosophila with a transformed genotype. In this study we investigated the radioadaptive response and hormesis by radiation-induced changed of the lifespan of different strains of Drosophila melanogaster, such as a wild type strain Canton-Sand strains with mutations in DNA damage response gene (homologue of GADD45), excision repair genes (homologues of XPF, XPC, PCNA) and double-strand breaks repair genes (homologues of RAD54, XRCC3, BLM). The exposure to irradiation at the dose rate of 40 cGy was performed chronically through the stages of fly development; an acute exposure at the dose rate of 30 Gy was applied to the adult stages of flies. Also, we investigated the resistance to acute gamma-radiation of Drosophila with conditional ubiquitous overexpression of genes that are involved in DNA damage recognition (homologues of GADD45, HUS1, CHK2), excision repair (homologues of XPF, XPC, AP-endonuclease-1) and double-strand break repair (homologues of BRCA2, XRCC3, KU80, WRNexo). In the wild type strain Canton-S, manifestation of the radioadaptive response and radiation hormesis were observed. In individuals with DNA repair gene mutations, no radioadaptive response was observed, or observed to a lesser extent than in wild type flies. Mifepristone--inducible transgene activation does not lead to an increase in resistance to acute irradiation by the parameters of lifespan of Drosophila. Overexpression of DNA repair genes led to a sharp decline in lifespan also in the absence of irradiation.
 ...
PMID:[Role of DNA repair genes in radiation-induced changes of lifespan of Drosophila melanogaster]. 2577 40

DNA repair declines with age and correlates with longevity in many animal species. In this study, we investigated the effects of GAL4-induced overexpression of genes implicated in DNA repair on lifespan and resistance to stress factors in Drosophila melanogaster. Stress factors included hyperthermia, oxidative stress, and starvation. Overexpression was either constitutive or conditional and either ubiquitous or tissue-specific (nervous system). Overexpressed genes included those involved in recognition of DNA damage (homologs of HUS1, CHK2), nucleotide and base excision repair (homologs of XPF, XPC and AP-endonuclease-1), and repair of double-stranded DNA breaks (homologs of BRCA2, XRCC3, KU80 and WRNexo). The overexpression of different DNA repair genes led to both positive and negative effects on lifespan and stress resistance. Effects were dependent on GAL4 driver, stage of induction, sex, and role of the gene in the DNA repair process. While the constitutive/neuron-specific and conditional/ubiquitous overexpression of DNA repair genes negatively impacted lifespan and stress resistance, the constitutive/ubiquitous and conditional/neuron-specific overexpression of Hus1, mnk, mei-9, mus210, and WRNexo had beneficial effects. This study demonstrates for the first time the effects of overexpression of these DNA repair genes on both lifespan and stress resistance in D. melanogaster.
...
PMID:Lifespan and Stress Resistance in Drosophila with Overexpressed DNA Repair Genes. 2647 11