Ago2-Dependent Processing Allows miR-451 to Evade the Global MicroRNA Turnover Elicited during Erythropoiesis

Kretov, Dmitry A.; Walawalkar, Isha A.; Mora-Martin, Alexandra; Shafik, Andrew M; Moxon, Simon; Cifuentes, Daniel

doi:10.1016/j.molcel.2020.02.020

Cited by 60 publications

(99 citation statements)

References 42 publications

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“…It has been previously shown that Argonauts generate small RNAs in a dicer-independent mechanism (60,63,64), and our data suggests that Ago1 in planarians may be involved in the dicer-independent processing and/or maintaining the stability of the itRFs.…”

Section: Ago1-based Processing Of Itrfs In S Mediterraneasupporting

confidence: 64%

“…Interestingly, tRF-5s that were implicated to undergo Dicer-based cleavage in other systems (75,76) also remained unaltered in Dicer KD suggesting that tRFs in planarians are Dicer-independent. However, in several systems, Argonauts have been shown to process of small RNAs in a dicer-independent pathway (60,63,64). Planarian Ago2 has been suggested to be critical for miRNA-based regulation (62) while the function of Ago1 remains unexplored.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive annotation and characterization of planarian tRNA and tRNA-derived fragments (tRFs)

Lakshmanan

Sujith

Bansal

et al. 2021

RNA

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tRNA-derived fragments (tRFs) have recently gained a lot of scientific interest due to their diverse regulatory roles in several cellular processes. However, their function in dynamic biological process such as development and regeneration remains unexplored. Here, we show that tRFs are dynamically expressed during planarian regeneration suggesting a possible role for these small RNAs in the regulation of regeneration. In order to characterise planarian tRFs, we first annotated 457 tRNAs in S.mediterranea combining two tRNA prediction algorithms. Annotation of tRNAs facilitated the identification of three main species of tRFs in planarians -the shorter tRF-5s and itRFs, and the abundantly expressed 5'-tsRNAs. Spatial profiling of tRFs in sequential transverse sections of planarians revealed diverse expression patterns of these small RNAs, including those that are enriched in the head and pharyngeal regions. Expression analysis of these tRF species revealed dynamic expression of these small RNAs over the course of regeneration suggesting an important role in planarian anterior and posterior regeneration. Finally, we show that 5'-tsRNA in planaria interact with all three SMEDWI proteins and an involvement of Ago1 in the processing of itRFs. In summary, our findings implicate a novel role for tRFs in planarian regeneration, highlighting their importance in regulating complex systemic processes. Our study adds to the catalogue of post-transcriptional regulatory systems in planarian, providing valuable insights on the biogenesis and the function of tRFs in neoblasts and planarian regeneration.

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Section: Ago1-based Processing Of Itrfs In S Mediterraneasupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Comprehensive annotation and characterization of planarian tRNA and tRNA-derived fragments (tRFs)

Lakshmanan

Sujith

Bansal

et al. 2021

RNA

View full text Add to dashboard Cite

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“…In addition, during erythropoiesis, miR‐144 targets DICER in a negative feedback loop, leading to the inhibition of canonical miRNA processing. Otherwise, DICER‐independent miR‐451 processing is undisturbed (Kretov et al, 2020).…”

Section: Mirna Biogenesismentioning

confidence: 99%

“…These intermediates are trimmed to 20–26 nt mature miRNAs (Pan et al, 2015; Yoda et al, 2013). During biogenesis, the passenger strand is not generated, which makes this miRNA a promising tool due to its limited off‐targets (Kretov et al, 2020). Konstantinova's group successfully used this backbone for the expression of siRNA targeting the HTT transcript, and a phase I/II clinical trial for this amiRNA in HD began this year.…”

Section: Artificial Mirna Scaffoldsmentioning

confidence: 99%

Artificial miRNAs as therapeutic tools: Challenges and opportunities

2021

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RNA interference (RNAi) technology has been used for almost two decades to study gene functions and in therapeutic approaches. It uses cellular machinery and small, designed RNAs in the form of synthetic small interfering RNAs (siRNAs) or vector‐based short hairpin RNAs (shRNAs), and artificial miRNAs (amiRNAs) to inhibit a gene of interest. Artificial miRNAs, known also as miRNA mimics, shRNA‐miRs, or pri‐miRNA‐like shRNAs have the most complex structures and undergo two‐step processing in cells to form mature siRNAs, which are RNAi effectors. AmiRNAs are composed of a target‐specific siRNA insert and scaffold based on a natural primary miRNA (pri‐miRNA). siRNAs serve as a guide to search for complementary sequences in transcripts, whereas pri‐miRNA scaffolds ensure proper processing and transport. The dynamics of siRNA maturation and siRNA levels in the cell resemble those of endogenous miRNAs; therefore amiRNAs are safer than other RNAi triggers. Delivered as viral vectors and expressed under tissue‐specific polymerase II (Pol II) promoters, amiRNAs provide long‐lasting silencing and expression in selected tissues. Therefore, amiRNAs are useful therapeutic tools for a broad spectrum of human diseases, including neurodegenerative diseases, cancers and viral infections. Recent reports on the role of sequence and structure in pri‐miRNA processing may contribute to the improvement of the amiRNA tools. In addition, the success of a recently initiated clinical trial for Huntington's disease could pave the way for other amiRNA‐based therapies, if proven effective and safe. This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action RNA in Disease and Development > RNA in Disease

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“…Drosha cleaves pre-miR-451, which is loaded directly into AGO2; it is responsible for 3′-end trimming and maturation of pre-miR-451. Poly(A)-specific ribonuclease (PARN) trims down the 3′ end of AGO2-cleaved pre-miR-451 to produce mature miR-451 [ 31 ]. Finally, XPO5 independent transport of pre-miRNA from the nucleus to cytoplasm has been described in the case of miR-320 family, as these miRNAs use the complex of XPO1 and PHAX (phosphorylated adaptor for RNA export) proteins for their transport [ 32 ].…”

Section: History Of Microrna Discoverymentioning

confidence: 99%

Epigenetic Regulation of MicroRNA Clusters and Families during Tumor Development

Gregorová

Vychytilova-Faltejskova

Ševčı́ková

2021

Cancers

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MicroRNAs are small non-coding single-stranded RNA molecules regulating gene expression on a posttranscriptional level based on the seed sequence similarity. They are frequently clustered; thus, they are either simultaneously transcribed into a single polycistronic transcript or they may be transcribed independently. Importantly, microRNA families that contain the same seed region and thus target related signaling proteins, may be localized in one or more clusters, which are in a close relationship. MicroRNAs are involved in basic physiological processes, and their deregulation is associated with the origin of various pathologies, including solid tumors or hematologic malignancies. Recently, the interplay between the expression of microRNA clusters and families and epigenetic machinery was described, indicating aberrant DNA methylation or histone modifications as major mechanisms responsible for microRNA deregulation during cancerogenesis. In this review, the most studied microRNA clusters and families affected by hyper- or hypomethylation as well as by histone modifications are presented with the focus on particular mechanisms. Finally, the diagnostic and prognostic potential of microRNA clusters and families is discussed together with technologies currently used for epigenetic-based cancer therapies.

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Ago2-Dependent Processing Allows miR-451 to Evade the Global MicroRNA Turnover Elicited during Erythropoiesis

Cited by 60 publications

References 42 publications

Comprehensive annotation and characterization of planarian tRNA and tRNA-derived fragments (tRFs)

Comprehensive annotation and characterization of planarian tRNA and tRNA-derived fragments (tRFs)

Artificial miRNAs as therapeutic tools: Challenges and opportunities

Epigenetic Regulation of MicroRNA Clusters and Families during Tumor Development

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