2. Academic Validation
  3. A ubiquitin ligase mediates target-directed microRNA decay independently of tailing and trimming

A ubiquitin ligase mediates target-directed microRNA decay independently of tailing and trimming

  • Science. 2020 Dec 18;370(6523):eabc9546. doi: 10.1126/science.abc9546.
Jaeil Han 1,  Collette A LaVigne 1,  Benjamin T Jones 1,  He Zhang 2 3,  Frank Gillett 1,  Joshua T Mendell 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. joshua.mendell@utsouthwestern.edu.
  • 5 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6 Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
PMID: 33184234 DOI: 10.1126/science.abc9546
Abstract

MicroRNAs (miRNAs) act in concert with Argonaute (AGO) proteins to repress target messenger RNAs. After AGO loading, miRNAs generally exhibit slow turnover. An important exception occurs when miRNAs encounter highly complementary targets, which can trigger a process called target-directed miRNA degradation (TDMD). During TDMD, miRNAs undergo tailing and trimming, suggesting that this is an important step in the decay mechanism. We identified a cullin-RING ubiquitin Ligase (CRL), containing the substrate adaptor ZSWIM8, that mediates TDMD. The ZSWIM8 CRL interacts with AGO proteins, promotes TDMD in a tailing and trimming-independent manner, and regulates miRNA expression in multiple cell types. These findings suggest a model in which the ZSWIM8 ubiquitin Ligase mediates TDMD by directing proteasomal decay of miRNA-containing complexes engaged with highly complementary targets.

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