Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of antigen receptor diversity in mammals is generated by V(D)J recombination. During this process DNA double strand breaks are introduced at recombination signals by lymphoid specific RAG1/2 proteins generating blunt ended signal ends and hairpinned coding ends. Rejoining of all DNA ends requires ubiquitously expressed DNA repair proteins, such as Ku70/86 and DNA ligase IV/XRCC4. In addition, the formation of coding joints depends on the function of the scid gene encoding the catalytic subunit of DNA-dependent protein kinase, DNA-PK(CS), that is somehow required for processing of coding end hairpins. Recently, it was shown that purified RAG1/2 proteins can cleave DNA hairpins in vitro, but the same activity was also described for a protein complex of the DNA repair proteins Nbs1/Mre11/Rad50. This leaves the possibility that either protein complex might be involved in coding end processing in V(D)J recombination. We have therefore analyzed V(D)J recombination in cells from patients with Nijmegen breakage syndrome, carrying a mutation in the nbs1 gene. We find that V(D)J recombination frequencies and the quality of signal and coding joining are comparable to wild-type controls, as analyzed by a cellular V(D)J recombination assay. In addition, we did not detect significant differences in CDR3 sequences of endogenous Ig lambdaL and kappaL chain gene loci cloned from peripheral blood lymphocytes of an NBS patient and of healthy individuals. These findings suggest that the Nbs1/Mre11/Rad50 complex is not involved in coding end processing of V(D)J recombination.
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PMID:Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome. 1128 95

DNA double-strand breaks, if unrepaired, may lead to the accumulation of chromosomal aberrations and eventually cancer cell formation. Components of the Rad50/NBS/Mre11 nuclease complex are essential for the effective repair of DNA double-stranded breaks. Here, we show that neocarzinostatin, a radiomimetic enediyne antibiotic, induces phosphorylation and nuclear focus formation of Mre11 and NBS1 through a cell cycle-independent mechanism. Furthermore, neocarzinostatin-induced Mre11 phosphorylation and nuclear focus formation are defective in AT and NBS cells, but not wild type cells. Our results suggest that ATM and NBS1 are required for the effective repair of neocarzinostatin-induced DNA double-strand breaks by both non-homologous end joining and homologous recombinational repair pathways.
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PMID:Neocarzinostatin induces Mre11 phosphorylation and focus formation through an ATM- and NBS1-dependent mechanism. 1213 16

In eukaryotes, DNA double-strand breaks (DSBs) can be repaired by either non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways. Rad50 protein is a component of the Rad50/NBS1/Mre11 nuclease complex that functions in both the NHEJ and recombinational repair of DNA DSBs. On the other hand, Rad51 protein, a homolog of bacterial RecA and a member of the Rad52 epistasis group, plays a crucial role exclusively in the recombinational repair pathway. We analyzed the effects of cell cycle progression and genetic background on the ionizing radiation (IR)-induced Rad51 and Rad50 repair focus formation. Herein, we demonstrated that IR-induced Rad51, but not Rad50, nuclear focus formation was cell cycle-dependent. Furthermore, IR-induced Rad51 focus formation was defective in AT and c-Abl(-/-) cells, but not wild type or NBS cells. A decreased and delayed formation of Rad51 foci-containing nuclei was observed in AT cells upon IR, whereas in c-Abl(-/-) cells a decreased but not delayed formation of Rad51 foci-containing nuclei was observed. In conclusion, effective and prompt IR-induced Rad51 focus formation is cell cycle-regulated and requires both ATM and c-Abl.
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PMID:Ionizing radiation-induced Rad51 nuclear focus formation is cell cycle-regulated and defective in both ATM(-/-) and c-Abl(-/-) cells. 1265 Sep 8

Camptothecin (CPT) and X-ray (XR) generate double-strand breaks (DSB) that can be processed by homologous or nonhomologous recombination. We studied the participation of proteins involved in recombination pathways and cell cycle control in the signal transduction between DNA damage and NF-kappaB. Cells harbouring mutated NBS, hMRE11, BRCA1 or MLH1 were analysed. NBS- and hMRE11-deficient cells present a classical kinetic of NF-kappaB induction after camptothecin treatment. When DSB are generated by XR, NBS-deficient cells exhibit a delayed and strongly reduced level of NF-kappaB induction, whereas the hMRE11 mutated cells do not induce NF-kappaB at all. This indicates an important role of the hMRE11/hRAD50/NBS complex in the signal transduction initiated by XR. In HCC1937 cells that express a truncated version of BRCA1, XR induces a very rapid and transient NF-kappaB activation, whereas CPT leads to a delayed activation suggesting that BRCA1 modulates the transduction pathways in different manners after these two stresses. Finally, we found that a proficient MMR pathway is essential to the NF-kappaB activation after both CPT and XR. These results indicate that DSB originating from XR or CPT do not induce NF-kappaB in a unique way. MMR participates in both cascades, whereas the hMRE11/hRAD50/NBS trimer is specifically involved in the response elicited by XR.
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PMID:Differential involvement of the hMRE11/hRAD50/NBS1 complex, BRCA1 and MLH1 in NF-kappaB activation by camptothecin and X-ray. 1295 88

DNA double-stranded breaks are the most detrimental form of DNA damage and, if not repaired properly, may lead to an accumulation of chromosomal aberrations and eventually tumorigenesis. Proteins of the Rad51/Rad52 epitasis group are crucial for the recombinational repair of DNA double-stranded breaks, whereas the Rad50/NBS1/Mre11 nuclease complex is involved in both the recombinational and the end-joining repair of DNA double-stranded breaks. Herein, we demonstrate that the chemotherapeutic enediyne antibiotic neocarzinostatin induced Rad51, but not NBS1, nuclear focus formation in a cell- cycle-dependent manner. Furthermore, neocarzinostatin-induced Rad51 foci formation revealed a slower kinetic change in AT cells, but not in wild-type or NBS cells. In summary, our results suggest that neocarzinostatin induces Rad51 focus formation through an ATM- and cell-cycle-dependent, but NBS1-independent, pathway.
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PMID:Neocarzinostatin-induced Rad51 nuclear focus formation is cell cycle regulated and aberrant in AT cells. 1457 40

Owing to their importance in normal cell division, DNA damage checkpoint and repair genes are often required for the earliest stages of embryzonic development. For example, conventional deletion of ATR, Chk1, Mad2, NBS, Rad50, BRCA1, BRCA2, or Rad51 leads to developmental arrest prior to gastrulation. While prior to arrest the number of cells extant in these embryos is low, procedures allowing rudimentary analysis of cell cycle checkpoints and genome integrity have been developed through culturing blastocysts in vitro. These procedures provide a small number of proliferating cells that can be analyzed for cell cycle progression, G2/M phase checkpoint responses, and gross chromosome abnormalities by mitotic spread preparation. Experiments such as these may help determine the essential functions of these genes in cell proliferation and early embryonic development. It is interesting to note that recently developed methods to introduce single-copy transgenes into one-cell zygotes via lentiviruses may provide a means to generate Cre/lox-conditional cell lines from these conventional knockouts.
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PMID:Analysis of cell cycle progression and genomic integrity in early lethal knockouts. 1518 55

Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation, chromosome instability and high frequency of malignancies. Since cellular features partly overlap with those of ataxia-telangiectasia (A-T), NBS was long considered an A-T clinical variant. NBS1, the product of the gene underlying the disease, contains three functional regions: the forkhead-associated (FHA) domain and BRCA1 C-terminus (BRCT) domain at the N-terminus, several SQ motifs (consensus phosphorylation sites by ATM and ATR kinases) at a central region and MRE11-binding region at the C-terminus. NBS1 forms a multimeric complex with hMRE11/hRAD50 nuclease at the C-terminus and recruits or retains them at the vicinity of sites of DNA damage by direct binding to histone H2AX, which is phosphorylated by ATM in response to DNA damage. The combination of the FHA/BRCT domains has a crucial role for the binding of NBS1 to H2AX. Thereafter, the NBS1 complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates, while it also might be involved in suppression of inter-chromosomal recombination even for V(D)J recombination. These processes collaborate with cell cycle checkpoints to facilitate DNA repair, while defects of these checkpoints in NBS cells are partial in nature. A possible explanation for these moderate defects are the redundancy of multiple checkpoint regulations in vertebrates, or the modulator role of NBS1, in which NBS1 amplifies ATM activation by accumulation of the MRN complex at damaged sites. This molecular link of NBS1 to ATM may explain the phenotypic similarity of NBS to A-T.
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PMID:NBS1 and its functional role in the DNA damage response. 1527 70

Mre11, together with Rad50 and Xrs2/NBS, plays pivotal roles in homologous recombination, repair of DNA double strand breaks (DSBs), activation of damage-induced checkpoint, and telomere maintenance. Here we demonstrate that the absence of Mre11 in yeast causes specific effects on regulation of a class of meiotic genes for spore development. Using DNA microarray assays to analyze yeast mutants defective for meiotic DSB formation, we revealed that the meiotic expression profile in the mre11Delta cells was generally unaffected when compared to the one in the wild-type strain, although the activation of about 90 meiotic genes were severely and specifically impaired in early meiosis. These defects were confirmed by northern and lacZ reporter gene assays. Interestingly, a substantial portion of the severely affected genes includes genes responsible for spore wall biogenesis, the defects of which may account for the fragile spore wall phenotype of the mre11Delta strain. The transcriptional deficiency was not observed in other DSB mutants such as rad50Delta, xrs2Delta, spo11Delta, and spo11Y135F, suggesting the transcriptional defect in mre11Delta is due to neither lack of meiotic DSB formation, nor disintegrity of Mre11-Rad50-Xrs2 complex. In addition, the deficiency of mre11Delta in gene activation was not alleviated by the deletion of RAD24. Therefore, it is unlikely that DNA damage checkpoint activation by mre11Delta caused transcriptional deficiency. We also found that a C-terminus DNA binding domain truncation mutant (mre11DeltaC49), which has meiosis-specific defects, exhibited transcriptional defects as observed in mre11Delta, whereas an N-terminal phosphoesterase mutant (mre11D16A) does not. Taken together, we propose that Mre11 is involved in the regulation of a specific class of genes during spore development through its C-terminus domain.
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PMID:Mre11 mediates gene regulation in yeast spore development. 1739 17

NBS1 is a member of the Mre11-Rad50-NBS1 complex, which plays a role in cellular responses to DNA damage and the maintenance of genomic stability. Transgenic mice models and clinical symptoms of NBS patients have shown that NBS1 exerts pleiotropic actions on the growth and development of mammals. The present study showed that after repression of endogenous NBS1 levels using short interfering RNA, hTERT-RPE cells demonstrated impaired proliferation and a poor response to IGF-1. NBS1 down-regulated cells displayed disturbances in periodical oscillations of cyclin E and A and delayed cell cycle progression. Remarkably, lower phosphorylation levels of c-Raf and diminished activity of Erk1/2 in response to IGF-1 suggest a link among NBS1, IGF-1 signaling and the Ras/Raf/MEK/ERK cascade. The functional relevance of NBS1 in mitogenic signaling and initiation of cell cycle progression were demonstrated in NBS1 down-regulated cells where IGF-1 had a limited ability to induce the FOS and CCND1 expressions. In conclusion, our findings provide strong evidence that NBS1 has a functional role in IGF-1 signaling for the promotion of cell proliferation via the Ras/Raf/MEK/ERK cascade.
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PMID:NBS1 is required for IGF-1 induced cellular proliferation through the Ras/Raf/MEK/ERK cascade. 1879 19

The conserved histone variant H2A.Z fulfills many functions by being an integral part of the nucleosomes placed at specific regions of the genome. Telomeres cap natural ends of chromosomes to prevent their recognition as double-strand breaks. At yeast telomeres, H2A.Z prevents the spreading of silent chromatin into proximal euchromatin. A role for H2A.Z in capping, however, has not been reported in any organism. Here, I uncover such a role for Drosophila H2A.Z. Loss of H2A.Z, through mutations in either its gene or the domino gene for the Swr1 chromatin-remodeling protein, suppressed the fusion of telomeres that lacked the protection of checkpoint proteins: ATM, ATR, and the Mre11-Rad50-NBS complex. Loss of H2A.Z partially restores the loading of the HOAP capping protein, possibly accounting for the partial restoration in capping. I propose that, in the absence of H2A.Z, checkpoint-defective telomeres adopt alternative structures, which are permissive for the loading of the capping machinery at Drosophila telomeres.
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PMID:Loss of the histone variant H2A.Z restores capping to checkpoint-defective telomeres in Drosophila. 1884 40


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