TENT2, TUT4, and TUT7 selectively regulate miRNA sequence and abundance

Yang, Acong; Ros, Xavier Bofill-De; Stanton, Ryan; Shao, Tiejuan; Villanueva, Patricia; Gu, Shuo

doi:10.1038/s41467-022-32969-8

Cited by 21 publications

(31 citation statements)

References 64 publications

(65 reference statements)

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“…Nonetheless, miRNA-mediated repression of mRNA does not always lead to mRNA degradation and may not be reflected on the gene expression level. In addition, while we show that TUT4/7 monouridylation of miRNAs is not required for maturation of group II miRNAs, monouridylation was previously shown to lead to tail-U-mediated repression (TUMR), modulating target recognition of miRNAs [ 26 , 35 ]. TUMR, thus, further complicates the miRNA–mRNA regulatory network.…”

Section: Discussionmentioning

confidence: 86%

“…Members of the let-7 miRNA family are among the miRNAs most increased in abundance, with 10 of 12 let-7 family miRNAs increased by at least 2-fold ( Figure 2 B, Table S5, Supplementary Files S5 and S6 ). The tumour suppressor let-7 miRNAs have previously been identified as TUT4/7 substrates [ 9 , 18 , 21 ], and a recent study similarly identified increased abundance of these miRNAs upon TUT4/7 deletion [ 35 ]. In addition, all members of the following miRNA families significantly increased in abundance by at least 2-fold: miR-941, miR-7, miR-19, miR-129, miR-4435, and miR-194 ( Figure 2 B).…”

Section: Resultsmentioning

confidence: 99%

“…Our data indicate that although TUT4/7 were previously shown to play a role in group II miRNA processing, this role can be fulfilled by other TENT enzymes. For example, TENT2 is thought to monoadenylate group II miRNAs in lieu of TUT4/7 [ 45 , 46 ], and that role was recently investigated [ 35 ]. In the case of group I miRNAs (let-7c and let-7e), expression levels in ΔTUT4/7 cells remained stable, with less than 2-fold changes in abundance ( Figure 2 C).…”

Section: Resultsmentioning

confidence: 99%

“…Finally, let-7a, which is present in three copies in the human genome (let-7a-1, let-7a-2, let-7a-3), is processed from both group I and group II pre-miRNAs and remained mostly stable in abundance, with a slight 1.6-fold increase in abundance in ΔTUT4/7 cells ( Figure 2 C). Although monouridylation was previously shown to play a major role in determining non-canonical miRNA target recognition [ 26 ] and the generation of 3′ isomiRs [ 35 ], monouridylation of group II precursor miRNAs may be considered a minor, non-essential role of TUT4/7, as group II miRNA family members are still processed to maturity in the absence of TUT4/7.…”

Section: Resultsmentioning

confidence: 99%

“…The deletion of TUT4/7 leads to reduced cell proliferation, as observed here and previously [ 17 ]. A different study showed no change in doubling time upon TUT4/7 deletion but an approximately 1.5-fold increased doubling time when TUT4/7 were knocked out in combination with TENT2 deletion [ 35 ]. We additionally found that TUT4/7 deletion leads to the loss of cellular adhesion, along with the formation of multicellular aggregates and spheroid-like structures.…”

Section: Discussionmentioning

confidence: 99%

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Terminal Uridylyltransferases TUT4/7 Regulate microRNA and mRNA Homeostasis

Zhang¹,

Frederick²,

Heinemann³

2022

Cells

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The terminal nucleotidyltransferases TUT4 and TUT7 (TUT4/7) regulate miRNA and mRNA stability by 3′ end uridylation. In humans, TUT4/7 polyuridylates both mRNA and pre-miRNA, leading to degradation by the U-specific exonuclease DIS3L2. We investigate the role of uridylation-dependent decay in maintaining the transcriptome by transcriptionally profiling TUT4/7 deleted cells. We found that while the disruption of TUT4/7 expression increases the abundance of a variety of miRNAs, the let-7 family of miRNAs is the most impacted. Eight let-7 family miRNAs were increased in abundance in TUT4/7 deleted cells, and many let-7 mRNA targets are decreased in abundance. The mRNAs with increased abundance in the deletion strain are potential direct targets of TUT4/7, with transcripts coding for proteins involved in cellular stress response, rRNA processing, ribonucleoprotein complex biogenesis, cell–cell signaling, and regulation of metabolic processes most affected in the TUT4/7 knockout cells. We found that TUT4/7 indirectly control oncogenic signaling via the miRNA let-7a, which regulates AKT phosphorylation status. Finally, we find that, similar to fission yeast, the disruption of uridylation-dependent decay leads to major rearrangements of the transcriptome and reduces cell proliferation and adhesion.

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Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Terminal Uridylyltransferases TUT4/7 Regulate microRNA and mRNA Homeostasis

Zhang¹,

Frederick²,

Heinemann³

2022

Cells

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Target‐directed microRNA degradation: Mechanisms, significance, and functional implications

Hiers,

Li,

Traugot

et al. 2024

WIREs RNA

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MicroRNAs (miRNAs) are small non‐coding RNAs that play a fundamental role in enabling miRNA‐mediated target repression, a post‐transcriptional gene regulatory mechanism preserved across metazoans. Loss of certain animal miRNA genes can lead to developmental abnormalities, disease, and various degrees of embryonic lethality. These short RNAs normally guide Argonaute (AGO) proteins to target RNAs, which are in turn translationally repressed and destabilized, silencing the target to fine‐tune gene expression and maintain cellular homeostasis. Delineating miRNA‐mediated target decay has been thoroughly examined in thousands of studies, yet despite these exhaustive studies, comparatively less is known about how and why miRNAs are directed for decay. Several key observations over the years have noted instances of rapid miRNA turnover, suggesting endogenous means for animals to induce miRNA degradation. Recently, it was revealed that certain targets, so‐called target‐directed miRNA degradation (TDMD) triggers, can “trigger” miRNA decay through inducing proteolysis of AGO and thereby the bound miRNA. This process is mediated in animals via the ZSWIM8 ubiquitin ligase complex, which is recruited to AGO during engagement with triggers. Since its discovery, several studies have identified that ZSWIM8 and TDMD are indispensable for proper animal development. Given the rapid expansion of this field of study, here, we summarize the key findings that have led to and followed the discovery of ZSWIM8‐dependent TDMD.This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA in Disease and Development > RNA in Development

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Substrate promiscuity of Dicer toward precursors of the let-7 family and their 3′-end modifications

Dadhwal,

Samy,

Bouvette

et al. 2024

Cell. Mol. Life Sci.

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The human let-7 miRNA family consists of thirteen members that play critical roles in many biological processes, including development timing and tumor suppression, and their levels are disrupted in several diseases. Dicer is the endoribonuclease responsible for processing the precursor miRNA (pre-miRNA) to yield the mature miRNA, and thereby plays a crucial role in controlling the cellular levels of let-7 miRNAs. It is well established that the sequence and structural features of pre-miRNA hairpins such as the 5′-phosphate, the apical loop, and the 2-nt 3′-overhang are important for the processing activity of Dicer. Exceptionally, nine precursors of the let-7 family (pre-let-7) contain a 1-nt 3′-overhang and get mono-uridylated in vivo, presumably to allow efficient processing by Dicer. Pre-let-7 are also oligo-uridylated in vivo to promote their degradation and likely prevent their efficient processing by Dicer. In this study, we systematically investigated the impact of sequence and structural features of all human let-7 pre-miRNAs, including their 3′-end modifications, on Dicer binding and processing. Through the combination of SHAPE structural probing, in vitro binding and kinetic studies using purified human Dicer, we show that despite structural discrepancies among pre-let-7 RNAs, Dicer exhibits remarkable promiscuity in binding and cleaving these substrates. Moreover, the 1- or 2-nt 3′-overhang, 3′-mono-uridylation, and 3′-oligo-uridylation of pre-let-7 substrates appear to have little effect on Dicer binding and cleavage rates. Thus, this study extends current knowledge regarding the broad substrate specificity of Dicer and provides novel insight regarding the effect of 3′-modifications on binding and cleavage by Dicer.

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TENT2, TUT4, and TUT7 selectively regulate miRNA sequence and abundance

Cited by 21 publications

References 64 publications

Terminal Uridylyltransferases TUT4/7 Regulate microRNA and mRNA Homeostasis

Terminal Uridylyltransferases TUT4/7 Regulate microRNA and mRNA Homeostasis

Target‐directed microRNA degradation: Mechanisms, significance, and functional implications

Substrate promiscuity of Dicer toward precursors of the let-7 family and their 3′-end modifications

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