Human RNase L tunes gene expression by selectively destabilizing the microRNA-regulated transcriptome

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Double-stranded RNA (dsRNA) is a potent activator of the mammalian innate immune system.
• Pseudokinase and endoribonuclease RNase L mediates intracellular RNA decay in response to dsRNA.
• RNase L plays a role in pathogen defense, cell growth regulation, and differentiation by degrading RNA targets.

Purpose of the Study:

• To develop a method for transcriptome-wide profiling of RNase L activity in human cells.
• To identify direct RNA targets and nontargets of RNase L.
• To elucidate the role of RNase L-dependent decay in regulating microRNA (miR)-mediated pathways and cellular processes.

Main Methods:

• Development of a transcriptome-wide profiling approach for RNase L activity.
• Identification of direct RNase L RNA targets and nontargets in human cells.
• Analysis of the overlap between RNase L targets and microRNA-regulated transcripts.

Main Results:

• Hundreds of direct RNA targets and nontargets of RNase L were identified.
• RNase L-dependent decay selectively impacts transcripts regulated by specific microRNAs (e.g., miR-17, miR-29, miR-200).
• RNase L was shown to mimic the suppressive effects of these microRNAs on cell proliferation and adhesion.

Conclusions:

• RNase L-dependent RNA decay destabilizes microRNA-regulated transcripts.
• RNase L functions as a suppressor of mammalian cell proliferation and adhesion.
• RNase L-dependent decay contributes to establishing an antiproliferative state by modulating the miR-regulated transcriptome.