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Oxazinomycin arrests RNA polymerase at the polythymidine sequences




TekijätPrajapati R.K., Rosenqvist P., Palmu K., Mäkinen J.J., Malinen A.M., Virta P., Metsä-Ketelä M., Belogurov G.A.

KustantajaOXFORD UNIV PRESS

Julkaisuvuosi2019

JournalNucleic Acids Research

Tietokannassa oleva lehden nimiNUCLEIC ACIDS RESEARCH

Lehden akronyymiNUCLEIC ACIDS RES

Vuosikerta47

Numero19

Aloitussivu10296

Lopetussivu10312

Sivujen määrä17

ISSN0305-1048

DOIhttps://doi.org/10.1093/nar/gkz782

Verkko-osoitehttps://academic.oup.com/nar/article/47/19/10296/5565285

Rinnakkaistallenteen osoitehttps://research.utu.fi/converis/portal/detail/Publication/44233423


Tiivistelmä
Oxazinomycin is a C-nucleoside antibiotic that is produced by Streptomyces hygroscopicus and closely resembles uridine. Here, we show that the oxazinomycin triphosphate is a good substrate for bacterial and eukaryotic RNA polymerases (RNAPs) and that a single incorporated oxazinomycin is rapidly extended by the next nucleotide. However, the incorporation of several successive oxazinomycins or a single oxazinomycin in a certain sequence context arrested a fraction of the transcribing RNAP. The addition of Gre RNA cleavage factors eliminated the transcriptional arrest at a single oxazinomycin and shortened the nascent RNAs arrested at the polythymidine sequences suggesting that the transcriptional arrest was caused by backtracking of RNAP along the DNA template. We further demonstrate that the ubiquitous C-nucleoside pseudouridine is also a good substrate for RNA polymerases in a triphosphorylated form but does not inhibit transcription of the polythymidine sequences. Our results collectively suggest that oxazinomycin functions as a Trojan horse substrate and its inhibitory effect is attributable to the oxygen atom in the position corresponding to carbon five of the uracil ring.

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