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The rates of the major steps in the molecular mechanism of RNase H1-dependent antisense oligonucleotide induced degradation of RNA. | LitMetric

The rates of the major steps in the molecular mechanism of RNase H1-dependent antisense oligonucleotide induced degradation of RNA.

Nucleic Acids Res

Department of Core Antisense Research, ISIS Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA 92010, USA.

Published: October 2015

AI Article Synopsis

  • * This study uses a minigene system to measure how long it takes for ASOs to enter cells, find their target RNA, and trigger degradation, highlighting the connection between these processes and how quickly cells produce and process RNA.
  • * Findings show that the speed of RNA degradation by ASOs varies between RNAs in the nucleus and those in the cytoplasm, and factors like RNase H1 levels and multiple binding sites can enhance the degradation rates of the targeted RNA.

Article Abstract

Antisense oligonucleotides (ASOs) are most commonly designed to reduce targeted RNA via RNase H1-dependent degradation, however kinetic parameters for ASO-mediated targeting and subsequent cleavage and degradation of RNA in living cells are poorly understood. In this manuscript we use an inducible minigene system to determine the time course of ASO activity in the cell. Estimates of the time required for the ASO to enter and traverse the cell, scan the target mRNA, bind the cognate site, recruit RNase H1 and initiate cleavage, are presented in the context of transcription and mRNA processing rates. Data are also presented which indicate that rates for RNase H1-dependent ASO-mediated degradation of the targeted RNAs are different for nuclear-retained versus RNAs exported to the cytoplasm and that the level of RNase H1 in the cell and cellular compartments is limiting to the rate of ASO activity. In both cellular compartments RNase H1 ASOs essentially double the endogenous rates of clearance of the target RNA. Overexpression of Escherichia coli RNase H1 or the presence of multiple cognate sites each further increase the rate of target RNA degradation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605327PMC
http://dx.doi.org/10.1093/nar/gkv920DOI Listing

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