Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A unique transgenic mouse line has undergone transgene integration in a very precise fashion. The phenotype displayed by mice of the line followed the predicted inheritance patterns for X-linked transgene insertion which has been confirmed. In order to investigate the mechanism of integration the DNA sequence of the transgene and cellular junctions have been determined. A comparison between wild type and transgenic mutant sequences at the site of insertion revealed that there was no loss or rearrangement of cellular DNA upon integration of the transgene. The cellular sequences at the transgene 5' and 3' joins are contiguous in the wild type. The integrant exists as a head to tail tandem dimer with minimal loss of sequence compared with the injected monomer. Analysis of the site of insertion has revealed a 5 bp homology between the 5' end of the transgene and the cellular sequences. In addition, adjacent to the site of insertion within the cellular sequences, there are several sequence motifs implicated in recombination events including a clustering of strong consensus sites of DNA topoisomerase type I and a region of homology to the human minisatellite consensus core sequence, the Escherichia coli Chi site and the meiotic recombination hotspot within the E beta gene of the murine major histocompatibility complex. This clustering of features is likely to have been factorial in the integrity of the insertion event. A model depicting the mechanism of this precise integration is proposed.
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PMID:A model for the mechanism of precise integration of a microinjected transgene. 867 44

Early in female mammalian embryogenesis, one of the two X chromosomes is inactivated to compensate the gene dosage between males and females. One of the features of X chromosome inactivation (XCI) is the late replication of the inactivated X chromosome. This study reports the identification, by competitive PCR of nascent DNA, of a replication origin in intron 2 of the human X-linked HPRT gene, that is functional only on the inactive X. Features frequently associated with replication origins, including a peak of enhanced DNA flexibility, a perfect match to the yeast ACS sequence, a 14/15 match to the Drosophila topoisomerase II consensus, and a 20/21 match to an initiation region consensus sequence, were identified close to the replication origin. The origin is located approximately 2 kb upstream of a matrix attachment region (MAR) and also contains two A:T-rich elements, thought to facilitate DNA unwinding.
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PMID:An inactive X specific replication origin associated with a matrix attachment region in the human X linked HPRT gene. 1577 6

DNA supercoiling factor (SCF) is a protein capable of generating negative supercoils in DNA in conjunction with topoisomerase II. To clarify the biological functions of SCF, we introduced a heritable SCF RNAi into Drosophila. Upon knockdown of SCF, we observed male lethality and male-specific reduction in the expression levels of X-linked genes. SCF functionally interacts with components of the MSL complex, which are required for dosage compensation via hypertranscription of the male X chromosome. Moreover, SCF colocalizes with the MSL complex along the male X chromosome. Upon overexpression of SCF, the male X chromosome had a bloated appearance. This phenotype was dependent on the histone acetyltransferase MOF and was suppressed by simultaneous overexpression of ISWI. These findings demonstrate that SCF plays a role in transcriptional activation via alteration of chromatin structure and provide evidence that SCF contributes to dosage compensation.
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PMID:DNA supercoiling factor contributes to dosage compensation in Drosophila. 1703 93

Drosophila maleless (MLE) is a member of helicase superfamily 2 and functions as a dosage compensation factor essential for the development of male flies. This function provides a good opportunity to investigate diverse biochemical activities associated with MLE in the context of a defined in vivo pathway, i.e., the transcriptional activation of X-linked genes. We have shown for the first time that MLE catalyzes the unwinding of both DNA and RNA and that MLE helicase activity is essential for its in vivo function. Also, we have provided evidence that MLE stimulates the transcriptional activity of roX2 on the X chromosome. We have also found that MLE interacts with dsDNA, topoisomerase II, and nucleosome. This observation supports a current model of dosage compensation: transcriptional activation of X-linked genes is causally associated with conformational change in the male X chromosome, subsequent to the targeted association of the dosage compensation complex (DCC).
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PMID:Regulation of inter- and intramolecular interaction of RNA, DNA, and proteins by MLE. 2022 59

In Drosophila, dosage compensation is mediated by the MSL complex, which binds numerous sites on the X chromosome in males and enhances the transcriptional rate of a substantial number of X-linked genes. We have determined that topoisomerase II (Topo II) is enriched on dosage compensated genes, to which it is recruited by association with the MSL complex, in excess of the amount that is present on autosomal genes with similar transcription levels. Using a plasmid model, we show that Topo II is required for proper dosage compensation and that compensated chromatin is topologically different from non-compensated chromatin. This difference, which is not the result of the enhanced transcription level due of X-linked genes and which represents a structural modification intrinsic to the DNA of compensated chromatin, requires the function of Topo II. Our results suggest that Topo II is an integral part of the mechanistic basis of dosage compensation.
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PMID:Topoisomerase II plays a role in dosage compensation in Drosophila. 2398 63