A Retrotransposon-Driven Dicer Isoform Directs Endogenous Small Interfering RNA Production in Mouse Oocytes

Flemr, Matyáš; Malı́k, Radek; Franke, Vedran; Nejepinska, Jana; Sedláček, Radislav; Vlahoviček, Kristian; Svoboda, Petr

doi:10.1016/j.cell.2013.10.001

Cited by 252 publications

(366 citation statements)

References 49 publications

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“…In addition, a natural Dicer isoform has been found in mouse oocytes, which lacks the N-terminal helicase domain, can efficiently generate siRNAs from long dsRNAs, and is sufficient for enhancing RNAi in cultured cells. This isoform is a consequence of a rodent-specific retrotransposon insertion and is present in Muridae family (Flemr et al, 2013). This demonstrates that, while the mammalian Dicer primarily dedicated to the miRNA pathway, a small change in a mammalian Dicer gene can restore RNAi activity.…”

Section: The N-terminal Helicase Domainmentioning

confidence: 94%

“…Notably, these experiments were performed using a long dsRNA substrate with blunt ends, whose processing by invertebrates Dicers is ATP-dependent (Zamore et al, 2000;Bernstein et al, 2001;Ketting et al, 2001;Nykanen et al, 2001;Zhang et al, 2002). Remarkably, deletion of the helicase domain results in high cleavage rate of long dsRNAs by human Dicer in vitro (Ma et al, 2008) as well as in vivo in murine and human cells (Flemr et al, 2013;Kennedy et al, 2015). Thus, the N-terminal helicase in mammalian Dicers has a different role in substrate recognition and processing than the helicase in invertebrate Dicers although the overall shapes of human and Drosophila Dicer proteins are similar (Lau et al, 2012).…”

Section: The N-terminal Helicase Domainmentioning

confidence: 99%

“…While the loss of the entire N-terminal helicase only slightly increases pre-miRNA processing activity in vitro (Ma et al, 2008), pre-miRNA-processing by recombinant Dicer in vitro is much faster than that of a perfect duplex (Ma et al, 2008;Chakravarthy et al, 2010). In vivo, a naturally occurring N-terminally truncated Dicer isoform can rescue miRNA biogenesis in Dicer -/-embryonic stem cells (ESCs) (Flemr et al, 2013 Feng et al, 2012;Lau et al, 2012;. This also indicates that the N-terminal helicase had acquired distinct roles in Dicer function in RNA silencing during evolution.…”

Section: Canonical Mirna Substratesmentioning

confidence: 99%

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Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

Pačes

Nič²,

Novotný³

et al. 2017

EFS3

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This report is the outcome of an EFSA procurement aiming at investigating and summarising the state of knowledge on (I) the mode-of-action of dsRNA and miRNA pathways, (II) the potential for nontarget gene regulation by dsRNA-derived siRNAs or miRNAs, (III) the determination of siRNA pools in plant tissues and the importance of individual siRNAs for silencing. The report is based on a comprehensive and systematic literature search, starting with the identification and retrieval of~190,000 publications related to the research area and further filtered down with keywords to produce focused collections used for subsequent screening of titles and abstracts. The report is comprised of an (I) Introduction to the field of small RNAs, (II) a Data and Methodologies section containing strategies used for literature search and study selection, and (III) the Results of the literature review organized according to the three main procurement tasks. The outcome of the first task reviews dsRNA and miRNA pathways in mammals (including humans), birds, fish, arthropods, annelids, molluscs, nematodes, and plants. Eight taxon-dedicated chapters are based on~1,400 cumulative references chosen from~10,000 inspected titles and abstracts. We review conserved and divergent aspects of small RNA pathways and dsRNA responses in animals and plants including structure and function of key proteins as well as four basic mechanisms: genome-encoded posttranscriptional regulations (miRNA), degradation of RNAs by short interfering RNA pools generated from long dsRNA (RNAi), transcriptional silencing, and sequence-independent responses to dsRNA. The outcome of the second task focuses on base pairing between small RNAs and their target RNAs and predictability of biological effects of small RNAs in animals and plants. The outcome of the last task reviews methodology, siRNA pools, and movement of small RNAs in plants. Potential transfer of small RNAs between species and circulating miRNAs in mammals is described in the final chapter.

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Section: The N-terminal Helicase Domainmentioning

confidence: 94%

Section: The N-terminal Helicase Domainmentioning

confidence: 99%

Section: Canonical Mirna Substratesmentioning

confidence: 99%

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Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

Pačes

Nič²,

Novotný³

et al. 2017

EFS3

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“…In contrast, others have found low abundance of viRNAs in mammalian somatic cells infected with various viruses, and only a modest effect of Dicer deficiency on viral replication, suggesting that RNAi is not an active mechanism of antiviral defence in most mammalian cell types (Parameswaran et al , 2010; Girardi et al , 2013; Backes et al , 2014; Bogerd et al , 2014; Schuster et al , 2017). RNAi may be particularly important in undifferentiated mammalian cells, and clear evidence of the existence of endogenous RNAi, dsRNA‐mediated RNAi (dsRNAi), or antiviral RNAi has been documented in oocytes, embryonic teratocarcinoma cell lines and mouse embryonic stem cells (mESCs), respectively (Billy et al , 2001; Flemr et al , 2013; Maillard et al , 2013). In mESCs, viral infection leads to the Dicer‐dependent emergence of viRNAs that associate with Ago2 and inhibit replication of a VSR‐deficient homologous virus (Maillard et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

et al. 2018

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In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG‐I‐like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG‐I, MDA5 and, the least‐studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP2 interferes with RNAi‐dependent suppression of gene expression. Conversely, genetic loss of LGP2 uncovers dsRNA‐mediated RNAi albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs. LGP2‐mediated antagonism of dsRNA‐mediated RNAi may help ensure that viral dsRNA substrates are preserved in order to serve as targets of antiviral ISG proteins.

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“…Studies in the female germ line confirm that although miRNA activity is suppressed in mouse oocytes, miRNAs are essential for zygotic development (51)(52)(53)(54). Recent studies confirm the oocytes, unlike somatic cells, express high levels of endogenous-small interfering RNAs that directly target many maternal RNAs and regulate early embryo development (55). In contrast to data on oocytes, loss of miRNAs in granulosa cells, the somatic cells of ovary and uterus, causes variable phenotypes ranging from reduced number of ovulations, defects in oviduct and uterine morphogenesis, and embryo implantation (56 -61).…”

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confidence: 96%

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

Wang

Graham

Hastings

et al. 2015

Journal of Biological Chemistry

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Background: DICER mediates microRNA production, and its functional role in gonadotropes is not known. Results: Deletion of Dicer in gonadotropes leads to suppression of gonadotropin synthesis and secretion and results in fertility defects. Conclusion: DICER-dependent microRNAs are critical for gonadotropin homeostasis and fertility. Significance: Understanding how microRNAs regulate gonadotropin homeostasis provides a new approach to enhance or block fertility in mammals.

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A Retrotransposon-Driven Dicer Isoform Directs Endogenous Small Interfering RNA Production in Mouse Oocytes

Cited by 252 publications

References 49 publications

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

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