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

Han, Jaeil; LaVigne, Collette A; Jones, Benjamin T.; Zhang, He; Gillett, Frank A; Mendell, Joshua T.

doi:10.1126/science.abc9546

Cited by 161 publications

(244 citation statements)

References 46 publications

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“…This is consistent with recent kinetic analysis which demonstrated that tailing is faster than 3’ trimming, so miRNAs are more likely to carry a tail as they age (8). TDMD is the most frequently-studied context in which tailing correlates with decay, yet recent work on TDMD suggests that tailing is correlative – not causative – of TDMD, and that conformational changes that promote decay of the Argonaute-miRNA complex also expose the miRNA 3’ end to TENTs (27, 28, 30, 31). However, in specific developmental contexts, tailing does promote wholesale miRNA turnover (32).…”

Section: Discussionmentioning

confidence: 99%

“…This process, known as target-directed miRNA degradation (TDMD), is induced by a handful of known naturally-occurring triggers, including tissue-specific lncRNAs and viral small RNAs that target a host miRNA (20)(21)(22)(23)(24)(25). While tailing was initially assumed to be causative of miRNA decay in this context, recent studies demonstrate examples in which tailing is dispensable for TDMD, suggesting that 3' tailing may be a symptom of miRNA 3' end display rather than an upstream regulatory event in TDMD (25)(26)(27)(28)(29).…”

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confidence: 99%

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Screening by deep sequencing reveals mediators of microRNA tailing inC. elegans

Prothro

Vieux

Palmer

et al. 2021

Preprint

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AbstractmicroRNAs are frequently modified by addition of untemplated nucleotides to the 3’ end, but the role of this tailing is often unclear. Here we characterize the prevalence and functional consequences of microRNA tailing in vivo, using the C. elegans model. MicroRNA tailing in C. elegans consists mostly of mono-uridylation of mature microRNA species, with rarer mono-adenylation which is likely added to microRNA precursors. Through a targeted RNAi screen, we discover that the TUT4/TUT7 gene family member CID-1 is required for uridylation, whereas the GLD2 gene family member F31C3.2 and, to a lesser extent, PAP-1 are required for adenylation. Thus, the TUT4/TUT7 and GLD2 gene families have broadly conserved roles in miRNA modification. We specifically examine the role of tailing in microRNA turnover. We determine half-lives of microRNAs after acute inactivation of microRNA biogenesis, revealing that half-lives are generally long (median=20.7h), as observed in other systems. Although we observe that tails are more prevalent on older microRNAs, disrupting tailing does not alter microRNA abundance or decay. Thus, tailing is not a global regulator of decay in C. elegans. Nonetheless, by identifying the responsible enzymes, this study lays the groundwork to explore whether tailing plays more specialized context- or miRNA-specific regulatory roles.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Screening by deep sequencing reveals mediators of microRNA tailing inC. elegans

Prothro

Vieux

Palmer

et al. 2021

Preprint

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“…43 Knocking out this conserved section of exon 3 in mice showed miR-7 upregulation in brain tissue. 37 Moreover, two independent groups recently reported that the ZSWIM8 Cullin-RING ligase mediates miR-7 degradation caused by Cyrano in a human cell line, 44,45 which indicates that Cyrano/ miR-7 regulation exists in multiple cellular contexts. These studies of Cyrano collectively indicate the challenges on dissecting the function of lncRNAs.…”

Section: Discussionmentioning

confidence: 99%

Lnc‐ing pluripotency maintenance and early differentiation in human pluripotent stem cells

Zhang

et al. 2021

The FASEB Journal

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Pluripotency maintenance and lineage differentiation are two major characteristics of human embryonic and induced pluripotent stem cells. The determination of self-renewal or differentiation is under the exquisite control of the gene regulatory network, which is composed of transcription factors, signaling pathways, metabolic factors, chromatin or histone modifiers, miRNAs, and lncRNAs. Growing evidence has shown that long noncoding RNAs (lncRNAs) play important roles in epigenetic, transcriptional, and posttranscriptional gene regulation during the cell fate determination of pluripotent stem cells. Here, we summarize recent reports of lncRNA functions in pluripotency maintenance/exit and the early germ layer specification of human pluripotent stem cells. We also illustrate four major lncRNA functional mechanisms according to different types of cofactors: chromatin or histone modifiers, transcription factors, canonical and noncanonical RNA-binding proteins, and miRNAs. Further understanding of lncRNA-based regulation will provide more insights into the drivers manipulating cell fate and promote the therapeutic and research potential of human embryonic and induced pluripotent stem cells.

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“…In humans, more than 2000 of them determine functions at the translational level miRNA-directed target degradation (MDTD) pathway of their target messengers 16,17 . In addition, new finding brought explanation for instability of some miRNAs, because the length of pairing with target could shorten the microRNA's life span 18,19 . miRNAs are degradated by cellular nucleases with pathway of target-directed miRNA degradation (TDMD) 20,21 .…”

Section: Micrornasmentioning

confidence: 99%