2. Academic Validation
  3. The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation

The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation

  • Science. 2020 Dec 18;370(6523):eabc9359. doi: 10.1126/science.abc9359.
Charlie Y Shi 1 2 3,  Elena R Kingston 1 2 3,  Benjamin Kleaveland 4,  Daniel H Lin 1 2 3,  Michael W Stubna 1 2 3,  David P Bartel 5 2 3
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 2 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 3 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 4 Department of Pathology and Lab Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 5 Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. dbartel@wi.mit.edu.
PMID: 33184237 DOI: 10.1126/science.abc9359
Abstract

MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread posttranscriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. We found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin Ligase. This and Other findings support a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin-proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING Ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand its inferred role in shaping miRNA levels in bilaterian Animals.

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