Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the nucleus of the cell, core RNA polymerase II (pol II) is associated with a large complex called the pol II holoenzyme (holo-pol). Transcription by core pol II in vitro on nucleosomal templates is repressed compared with that on templates of histone-free naked DNA. We found that the transcriptional activity of holo-pol, in contrast to that of core pol II, is not markedly repressed on chromatin templates. We refer to this property of holo-pol as chromatin-dependent coactivation (CDC). Here we show that DNA topoisomerase IIalpha is associated with the holo-pol and is a required component of CDC. Etoposide and ICRF-193, specific inhibitors of topoisomerase II, blocked transcription on chromatin templates, but did not affect transcription on naked templates. Addition of purified topoisomerase IIalpha reconstituted CDC activity in reactions with core pol II. These findings suggest that transcription on chromatin templates results in the accumulation of superhelical tension, making the relaxation activity of topoisomerase II essential for productive RNA synthesis on nucleosomal DNA.
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PMID:DNA topoisomerase IIalpha is required for RNA polymerase II transcription on chromatin templates. 1157 92

The MLL gene is frequently involved in chromosomal translocations associated with high-risk acute leukaemia. Infant and therapy-related acute leukaemia patients display chromosomal breakpoints preferentially clustered in the telomeric portion of the MLL breakpoint cluster region (SCII). Here, we demonstrate that SCII colocalizes with a gene-internal promoter element in the mouse and human MLL gene, respectively. The mRNA generated encodes an N-terminally truncated version of MLL that still exhibits many functional regions, including the C-terminal SET-domain. Etoposide-induced DNA double-strand breaks colocalize with the binding site of RNA polymerase II and the transcription initiation region, but not with a nearby Topo II consensus sequence. Thus, the observed genomic instability of the human MLL gene is presumably linked to transcriptional processes. The consequences of this novel finding for the creation of chromosomal translocations, the biology of the MLL protein and for MLL-mediated acute leukaemia are discussed.
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PMID:Transcription linked to recombination: a gene-internal promoter coincides with the recombination hot spot II of the human MLL gene. 1698 45

Being involved in an anti-Flaviviridae Project, and because of the role played by benzimidazole derivatives as promising inhibitors of the HCV helicase and RNA polymerase, as well as of the Zn finger transcription factor, we synthesized a new series of 2-arylbenzimidazoles and evaluated them for antiviral activity, as well as for antiproliferative activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Flaviviruses and Pestiviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae). Compounds 15, 28 and 29 resulted moderately active only against Yellow Fever Virus (a Flavivirus) (range 6-27 microM), whereas none of the title benzimidazoles showed any antiviral activity at concentrations not cytotoxic for the resting cell monolayers. Compounds were also tested for antiproliferative activity against a panel of exponentially growing cell lines derived from human haematological and solid tumors. Several new benzimidazoles turned out active. Among them, compound 27 was the most potent against human haematologic and solid tumor cells and turned out to be as potent as Etoposide and more potent than 6-mercaptopurine (6-MP), used as reference antitumor agents.
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PMID:2-Arylbenzimidazoles as antiviral and antiproliferative agents. Part 1. 1899 46

Telomeric repeat-containing RNAs (TERRAs) are long noncoding RNAs transcribed from subtelomeres toward telomeric repeat tracts, which have been implicated in telomere protection and heterochromatin formation. Genotoxic stress leads to upregulation of TERRAs. However, the mechanism of DNA damage-mediated TERRA induction remains elusive. Here, we treated HeLa cells with etoposide, a DNA double-strand break-generating agent, for various times and monitored the levels of TERRAs. Etoposide treatment led to a gradual time-dependent increase in TERRAs. Etoposide-mediated induction was evident in many TERRAs arising from various chromosome loci, including 20q and XpYp. Chromatin immunoprecipitation assays revealed no significant changes in the occupancy of RNA polymerase II at telomeres upon etoposide treatment. Interestingly, TERRAs arising from 20q, XpYp, 10q, and 13q degraded at slower rates in cells treated with etoposide, while degradation rates of TERRAs from many loci tested were nearly identical in both etoposide- and mock-treated cells. Telomere damage occurred from early time points of etoposide treatment, but telomere lengths and abundance of telomeric repeat-binding factor 2 (TRF2) at telomeres remained unchanged. In summary, etoposide treatment led to telomere damage and TERRA accumulation, but telomere lengths and TRF2-mediated telomere integrity were maintained. Etoposide-mediated TERRA accumulation could be attributed partly to RNA stabilization. These findings may provide insight into the post-transcriptional regulation of TERRAs in response to DNA damage.
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PMID:Increased amounts and stability of telomeric repeat-containing RNA (TERRA) following DNA damage induced by etoposide. 3175 21