DNA topoisomerase I in the mouse central nervous system: Age and sex dependence

Plaschkes, Inbar; Silverman, F. William; Priel, Esther

doi:10.1002/cne.20793

Cited by 21 publications

(29 citation statements)

References 35 publications

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“…With regard to TOP1, in addition to obtaining identical results using two independently generated monoclonal antibodies, our observation that TOP1 is localized to the nucleolus and nucleoplasm is consistent with other studies on the distribution of this enzyme within the nucleolus [23], and nucleus, including observations of GFP-tagged TOP1 in living human cells [24,25]. It should be noted that in one study [34], cytoplasmic TOP1 staining was observed in the mouse Purkinje neurons. However, in another study [35] TOP1 staining was observed in the nucleolus of postnatal rat Purkinje neurons, consistent with our findings.…”

Section: The Mrn-complex and Topoisomerase I Are Also Concentrated Insupporting

confidence: 89%

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ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

et al. 2007

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The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons. Surprisingly, while ATM plays a criticial role in the cellular reponse to DNA damage, previous studies have localized ATM to the cytoplasm of rodent and human Purkinje neurons. Here we show that ATM is primarily localized to the nucleus in cerebellar Purkinje neurons in postmortem human brain tissue samples, although some light cytoplasmic ATM staining was also observed. No ATM staining was observed in brain tissue samples from AT patients, verifying the specificity of the antibody. We also found that antibodies against components of the Mre11/Rad50/Nbs1 (MRN) complex showed strong staining in Purkinje cell nuclei. However, while ATM is present in both the nucleoplasm and nucleolus, MRN proteins are excluded from the nucleolus. We also observed very high levels of topoisomerase 1 (TOP1) in the nucleus, and specifically the nucleolus, of human Purkinje neurons. Our results have direct implications for understanding the mechanisms of neurodegeneration in AT and AT-like disorder.

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Section: The Mrn-complex and Topoisomerase I Are Also Concentrated Insupporting

confidence: 89%

“…However, in another study [35] TOP1 staining was observed in the nucleolus of postnatal rat Purkinje neurons, consistent with our findings. Whether the discrepant observations [34] represent a species difference, a methodological difference, or non-specific staining remains to be determined.…”

Section: The Mrn-complex and Topoisomerase I Are Also Concentrated Inmentioning

confidence: 99%

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

et al. 2007

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“…Mouse brain shows substantial levels of topo I activity varying among different brain regions (Plaschkes et al, 2005). Immunohistochemistry shows that the highest topo I levels are observed in inhibitory neurons.…”

Section: Jsmentioning

confidence: 99%

“…Eukaryotic type I topoisomerase (topo IB) plays important roles in DNA replication, RNA transcription, DNA recombination, chromosome condensation, and the maintenance of genomic stability (Champoux, 2001;Wang, 2002). Immunohistochemical analysis in selected mouse brain regions reveals that a significant level of topo I activity is present in the brain, and the level of topo I activity varies among different brain regions (Plaschkes et al, 2005). The cerebellum, visual cortex, and the striatum exhibit higher topo I activity than the hippocampus and hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

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Seizure Suppression bytop1Mutations inDrosophila

Song

Tanouye

2007

J. Neurosci.

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DNA topoisomerase I is an essential nuclear enzyme involved in resolving the torsional stress associated with DNA replication, transcription, and chromatin condensation. Here we report the discovery of a seizure-suppressor mutant, top1 JS , which suppresses seizures in a Drosophila model of human epilepsy. A P-element mutagenesis screen using easily shocked seizure-sensitive mutant as a genetic background identified top1 JS , which plays a novel role in regulating nervous system excitability. Plasmid rescue, excision, complementation, and sequencing analyses verified that top1JS results from a P-element insertion in the 5Ј untranslated region. Quantitative reverse transcription analysis on wild-type and mutant fly heads showed that the top1 JS mutation causes reduced transcription level in the CNS, suggesting a partial loss-of-function mutation. Electrophysiological experiments revealed normal seizure thresholds in top1 JS mutants, which are different from other seizure suppressors identified previously, suggesting a novel mechanism underlying seizure suppression by top1 JS . The pharmacological camptothecin feeding experiment and cell death analysis suggested that the seizure suppression by top1 JS may occur via increased neuronal apoptosis. Furthermore, overexpression of the DIAP1 (Drosophila inhibitor of apoptosis 1) gene rescues top1 JS suppression, providing additional support for a neural apoptosis suppression mechanism. The top1 JS mutation is the first viable partial loss-of-function mutation identified in higher eukaryotes, and the results presented here point to a novel function for topo I in construction and/or maintenance of circuits required for seizure propagation in vivo.

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Glutamate Regulates the Activity of Topoisomerase I in Mouse Cerebellum

et al. 2008

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Topoisomerase I (topo I) is a nuclear enzyme which participates in most DNA transactions. It was shown to be inhibited in depolarized neurons by poly adenosine diphosphate (ADP)-ribosylation of the enzyme protein. We demonstrated previously an age and sex dependent topo I activity and enzyme protein level in the various regions of mouse brain. A specific distribution pattern of topo I was observed and the inhibitory neurons exhibited the highest enzyme activity and protein level in both the nucleus and the cytoplasm. Here, we show that neurotransmitters (glutamate and gamma-aminobutyric acid (GABA)) regulate the activity of topo I in mouse cerebellum sections. Glutamate exhibited a significant time-dependent inhibition of topo I activity but no effect of the enzyme protein level. GABA in contrary only slightly and transiently inhibited topo I activity. The inhibitory effect of glutamate was mediated by Ca(+2) and by ADP-ribosylation of topo I protein and the glutamate ionotropic receptors were involved. Glutamate also diminished the inhibitory effect of topotecan on topo I. These results point to distinct and highly specific effects of the major neurotransmitters on topo I activity in the cerebellum suggesting that topo I possesses a specific role in the brain which differs from its known biological functions.

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DNA topoisomerase I in the mouse central nervous system: Age and sex dependence

Cited by 21 publications

References 35 publications

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

Seizure Suppression bytop1Mutations inDrosophila

Glutamate Regulates the Activity of Topoisomerase I in Mouse Cerebellum

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