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)

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

Various inhibitors of histone deacetylase (HDAC) activity can sensitize drug resistant cancer cells to chemotherapeutic agents. However, the mechanisms underlying such effects of distinct HDAC inhibitors (HDACi) remain poorly understood. Here we show that both the HDACi trichostatin A and valproic acid induced a sensitization of multidrug-resistant cancer cells to the topoisomerase II inhibitor etoposide/VP16. This effect was associated with increased acetylation of certain lysines on histones H3 and H4, including lysine 16 on histone H4 (H4K16). Overexpression of the histone acetyltransferase hMOF, known to target H4K16, was sufficient to mimic HDACi treatment on sensitization and H4K16 acetylation, and importantly, small-interfering RNA (siRNA)-mediated knockdown of hMOF abolished the HDACi-mediated sensitizing effects as well as the increase in H4K16 acetylation. Conversely, siRNA-mediated knockdown of the H4K16 deacetylase SIRT1 mimicked HDACi treatment whereas overexpression of SIRT1 abolished H4K16 acetylation and significantly reduced the sensitizing effects of HDACi. Interestingly, the effects of hMOF on H4K16 acetylation and sensitization to the topoisomerase II inhibitor could be directly counteracted by exogenous expression of increasing amounts of SIRT1 and vice versa. Our study results suggest that hMOF and SIRT1 activities are critical parameters in HDACi-mediated sensitization of multidrug-resistant cancer cells to topoisomerase II inhibitor and increased H4K16 acetylation.
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PMID:Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide. 2011 81

Condensins associate with DNA and shape mitotic chromosomes. Condensins are enriched nearby highly expressed genes during mitosis, but how this binding is achieved and what features associated with transcription attract condensins remain unclear. Here, we report that condensin accumulates at or in the immediate vicinity of nucleosome-depleted regions during fission yeast mitosis. Two transcriptional coactivators, the Gcn5 histone acetyltransferase and the RSC chromatin-remodelling complex, bind to promoters adjoining condensin-binding sites and locally evict nucleosomes to facilitate condensin binding and allow efficient mitotic chromosome condensation. The function of Gcn5 is closely linked to condensin positioning, since neither the localization of topoisomerase II nor that of the cohesin loader Mis4 is altered in gcn5 mutant cells. We propose that nucleosomes act as a barrier for the initial binding of condensin and that nucleosome-depleted regions formed at highly expressed genes by transcriptional coactivators constitute access points into chromosomes where condensin binds free genomic DNA.
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PMID:Nucleosome eviction in mitosis assists condensin loading and chromosome condensation. 2726 25