| Title | The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation. |
| Publication Type | Journal Article |
| Year of Publication | 2020 |
| Authors | Shi CY, Kingston ER, Kleaveland B, Lin DH, Stubna MW, Bartel DP |
| Journal | Science |
| Volume | 370 |
| Issue | 6523 |
| Date Published | 2020 12 18 |
| ISSN | 1095-9203 |
| Keywords | Animals, Argonaute Proteins, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Drosophila, Drosophila Proteins, Elongin, Gene Knockdown Techniques, Humans, K562 Cells, Mice, MicroRNAs, NIH 3T3 Cells, Proteolysis, RNA Stability, RNA, Long Noncoding, Ubiquitin-Protein Ligases |
| 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. |
| DOI | 10.1126/science.abc9359 |
| Alternate Journal | Science |
| PubMed ID | 33184237 |
| PubMed Central ID | PMC8356967 |
| Grant List | R35 GM118135 / GM / NIGMS NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States |
Related Faculty:
Benjamin Kleaveland, M.D., Ph.D.