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Statements

Subject Item
n2:RIV%2F00209805%3A_____%2F14%3A%230000508%21RIV15-GA0-00209805
rdf:type
skos:Concept n7:Vysledek
rdfs:seeAlso
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931720/
dcterms:description
Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II mediated transcription. Several pharmacological CDK inhibitors are currently in clinical trials as potential cancer therapeutics and some of them also exhibit antiviral effects. Olomoucine II and roscovitine were described as effective antiviral agents that inhibit replication of a broad range of wild type human viruses. Olomoucine II and roscovitine show high selectivity for CDK7 and CDK9, with important functions in the regulation of RNA polymerase II transcription. RNA polymerase II is necessary for viral transcription and following replication in cells. We analyzed the effect of inhibition of CDKs by olomoucine II on gene expression from viral promoters and compared its effect to widely-used roscovitine. We found that both roscovitine and olomoucine II blocked the phosphorylation of RNA polymerase II C-terminal domain. However the repression of genes regulated by viral promoters was strongly dependent on gene localization. Both roscovitine and olomoucine II inhibited expression only when the viral promoter was not integrated into chromosomal DNA. In contrast, treatment of cells with genome-integrated viral promoters increased their expression even though there was decreased phosphorylation of the C-terminal domain of RNA polymerase II. To define the mechanism responsible for decreased gene expression after pharmacological CDK inhibitor treatment, the level of mRNA transcription from extrachromosomal DNA was determined. Interestingly, our results showed that inhibition of RNA polymerase II C-terminal domain phosphorylation increased the number of transcribed mRNAs. However, some of these mRNAs were truncated and lacked polyadenylation, which resulted in decreased translation. These results suggest that phosphorylation of RNA polymerase II C-terminal domain is critical for linking transcription and posttrancriptional processing of mRNA expressed from extrachromosomal DNA. Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II mediated transcription. Several pharmacological CDK inhibitors are currently in clinical trials as potential cancer therapeutics and some of them also exhibit antiviral effects. Olomoucine II and roscovitine were described as effective antiviral agents that inhibit replication of a broad range of wild type human viruses. Olomoucine II and roscovitine show high selectivity for CDK7 and CDK9, with important functions in the regulation of RNA polymerase II transcription. RNA polymerase II is necessary for viral transcription and following replication in cells. We analyzed the effect of inhibition of CDKs by olomoucine II on gene expression from viral promoters and compared its effect to widely-used roscovitine. We found that both roscovitine and olomoucine II blocked the phosphorylation of RNA polymerase II C-terminal domain. However the repression of genes regulated by viral promoters was strongly dependent on gene localization. Both roscovitine and olomoucine II inhibited expression only when the viral promoter was not integrated into chromosomal DNA. In contrast, treatment of cells with genome-integrated viral promoters increased their expression even though there was decreased phosphorylation of the C-terminal domain of RNA polymerase II. To define the mechanism responsible for decreased gene expression after pharmacological CDK inhibitor treatment, the level of mRNA transcription from extrachromosomal DNA was determined. Interestingly, our results showed that inhibition of RNA polymerase II C-terminal domain phosphorylation increased the number of transcribed mRNAs. However, some of these mRNAs were truncated and lacked polyadenylation, which resulted in decreased translation. These results suggest that phosphorylation of RNA polymerase II C-terminal domain is critical for linking transcription and posttrancriptional processing of mRNA expressed from extrachromosomal DNA.
dcterms:title
Inhibition of post-transcriptional RNA processing by CDK inhibitors and its implication in anti-viral therapy Inhibition of post-transcriptional RNA processing by CDK inhibitors and its implication in anti-viral therapy
skos:prefLabel
Inhibition of post-transcriptional RNA processing by CDK inhibitors and its implication in anti-viral therapy Inhibition of post-transcriptional RNA processing by CDK inhibitors and its implication in anti-viral therapy
skos:notation
RIV/00209805:_____/14:#0000508!RIV15-GA0-00209805
n4:aktivita
n6:I n6:S n6:P
n4:aktivity
I, P(ED2.1.00/03.0101), P(GBP206/12/G151), P(LO1204), S
n4:cisloPeriodika
92
n4:dodaniDat
n10:2015
n4:domaciTvurceVysledku
n8:5395488 n8:5361850 n8:9637419 n8:1330586 n8:4001818
n4:druhVysledku
n5:J
n4:duvernostUdaju
n19:S
n4:entitaPredkladatele
n12:predkladatel
n4:idSjednocenehoVysledku
21852
n4:idVysledku
RIV/00209805:_____/14:#0000508
n4:jazykVysledku
n11:eng
n4:klicovaSlova
roscovitine; olomoucine II; phosphorylation; extrachromosomal DNA
n4:klicoveSlovo
n9:phosphorylation n9:extrachromosomal%20DNA n9:roscovitine n9:olomoucine%20II
n4:kodStatuVydavatele
US - Spojené státy americké
n4:kontrolniKodProRIV
[7351A8B2540F]
n4:nazevZdroje
PloS one
n4:obor
n13:FD
n4:pocetDomacichTvurcuVysledku
5
n4:pocetTvurcuVysledku
9
n4:projekt
n18:ED2.1.00%2F03.0101 n18:LO1204 n18:GBP206%2F12%2FG151
n4:rokUplatneniVysledku
n10:2014
n4:svazekPeriodika
9
n4:tvurceVysledku
Holčáková, Jitka Nekulová, Marta Vojtěšek, Bořivoj Hrstka, Roman Müller, Petr
n4:wos
000331717900066
s:issn
1932-6203
s:numberOfPages
10
n17:doi
10.1371/journal.pone.0089228