The Microprocessor controls the activity of mammalian retrotransposons

Heras, Sara R.; Macías, Sara; Plass, Mireya; Fernández, Noemí; Cano, David A.; Eyras, Eduardo; García‐Pérez, José L.; Cáceres, Javier F.

doi:10.1038/nsmb.2658

Cited by 105 publications

(117 citation statements)

References 71 publications

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“…Our findings complement previous work on L1 post-transcriptional regulation by Caceres and colleagues 26,38 , which identified multiple direct binding sites in the L1 5′ UTR for the microprocessorcomplex subunit DGCR8 (ref. 38), which binds and cleaves L1 RNA 26 .…”

Section: Discussionsupporting

confidence: 91%

“…38), which binds and cleaves L1 RNA 26 . Our results expand this work and suggest a scenario in which DGCR8 binds to double-stranded RNA structures of the 5′ UTR of L1 RNA and cleaves L1 in the nucleus; L1 transcripts that escape DGCR8-mediated control are transported out of the nucleus, where a second miR-mediated mechanism regulates their expression levels and represses their effects in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, depletion of three of the main proteins involved in miR biogenesis and miR function (Dicer, DGCR8 and Ago) in different cell types results in significantly increased L1 activity 26,27 . To test whether miRs regulate L1 activity in somatic cells, we designed a lentiviral-based knockdown strategy in which libraries of expressed short hairpin RNAs (shRNAs) with anti-miR activity were used to neutralize endogenous miRs in HeLa cells.…”

Section: Identification Of Retrotransposition-repressor Mirsmentioning

confidence: 99%

“…Somatic cells attenuate element mobilization by DNA methylation of the L1 promoter 23 . Other methods of regulation are mediated by APOBEC proteins 24,25 , microprocessor interactions 26 and Ago-mediated RNA interference in mouse embryonic stem cells 27 . L1-promoter silencing is greatly attenuated, and L1 transcription is reactivated in hypomethylated cells, such as cancer cells and tumor-initiating cells, and is also reactivated during reprogramming [28][29][30] .…”

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confidence: 99%

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miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Hamdorf

Idica

Zisoulis

et al. 2015

Nat Struct Mol Biol

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VOLUME 22 NUMBER 10 OCTOBER 2015 nature structural & molecular biology a r t i c l e s microRNAs (miRs) are a class of small (~22-nt) genomically encoded molecules that inhibit translational initiation and stimulate decay of mRNA targets 1,2 . miRs are transcribed by RNA polymerase II and processed by the RNase III enzymes-Dicer and Drosha with its binding partner, DGCR8-to produce short double-stranded RNAs in the nucleus. One strand associates with the Argonaute (Ago) protein, thus forming the miR-mediated silencing complex (miRISC). miRs guide the pairing of miRISC, with imperfect complementarity, to sequences in target mRNAs, thus resulting in their subsequent destabilization and translational repression of the target 3 . The 'seed sequence' , at nucleotides 2-8, is a key determinant for miRISC-target recognition 4,5 . Recent data have shown that 35-40% of miR-binding sites are found in 3′ untranslated regions (UTRs), 40-50% in coding regions and <5% in 5′-UTR regions of mRNAs 6,7 . More than 60% of the human transcriptome has been predicted to be under miR regulation, thus making this post-transcriptional control pathway as important as protein pathways in the regulation of cell functions 2 . It is clear that miRs have essential roles in regulating diverse functions in normal and diseased cells 8,9 .L1 belongs to the most abundant class of autonomous transposable elements 10 . Human L1 contains two open reading frames, ORF1 and ORF2, which encode a protein with RNA-binding and nucleotide acid-chaperone activity (ORF1) 11 and a protein with endonuclease and reverse-transcriptase activities (ORF2) 12-15 , respectively. L1 mobilizes replicatively from one location in the genome to another by a 'copy-and-paste' mechanism, and it has been proposed to be a remnant of an ancient retrovirus 12,16 . Active and inactive L1s have been implicated in the evolution of mammalian genomes and are linked to cell-based diseases, including cancer [17][18][19] . In addition, somatic L1 insertions are biased toward regions of cancer-specific DNA hypomethylation, thus suggesting that L1 insertions may provide a selective advantage during tumorigenesis 20 . Mechanisms that operate at different levels in gene-expression hierarchies have been selected to control transposition-mediated mutagenesis and mitigate the potential negative effects of newly inserted elements. In germ cells, a specific small-RNA subtype (piwi-interacting RNAs (piRNAs)) efficiently counteracts L1 activity, but these RNAs are not expressed in nongerm cells 21,22 . Somatic cells attenuate element mobilization by DNA methylation of the L1 promoter 23 . Other methods of regulation are mediated by APOBEC proteins 24,25 , microprocessor interactions 26 and Ago-mediated RNA interference in mouse embryonic stem cells 27 . L1-promoter silencing is greatly attenuated, and L1 transcription is reactivated in hypomethylated cells, such as cancer cells and tumor-initiating cells, and is also reactivated during reprogramming [28][29][30] . Because miRs act as regulators of g...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Retrotransposition-repressor Mirsmentioning

confidence: 99%

mentioning

confidence: 99%

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miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Hamdorf

Idica

Zisoulis

et al. 2015

Nat Struct Mol Biol

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show abstract

“…147 Furthermore, the Drosha-DGCR8 microprocessor that is necessary for biogenesis of miRNA can negatively regulate L1 and Alu retrotransposition. 148 Piwi proteins are animal-specific members of the Argonaute protein family that associate with piwi-interacting RNAs (piRNAs) to mediate small RNA-dependent gene regulation, particularly of retrotransposons in the germ line. 149 Piwi proteins bind cleavage products of single-stranded RNA produced from genomic sites referred to as piRNA clusters and use their slicer activity to cleave complementary RNA molecules, which then generates piRNAs of the complementary sequences that can be used to process additional piRNAs from piRNA cluster transcripts.…”

Section: Restriction Of Autonomous Mammalian Retrotransposonsmentioning

confidence: 99%

Consequences of ongoing retrotransposition in mammalian genomes

Maxwell

2014

AGG

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Abstract:Retrotransposons can have significant influences on gene expression and genome stability through their ability to integrate reverse-transcript copies of their sequences at new genomic locations by retrotransposition. These elements have been long known to retrotranspose in mammalian germ cells to give rise to inherited insertion alleles, but more recent work has also shown that retrotransposition can occur in mammalian somatic cells, particularly in brain tissue and tumors. Retrotransposition makes appreciable contributions to spontaneous diseasecausing alleles in humans and a more significant contribution to spontaneous mutations in mice. Genome-wide studies have found high levels of polymorphic retrotransposon insertions in human populations that are consistent with ongoing retrotransposition. Many insertions do not disrupt exons, but insertions into introns or flanking genes can alter gene expression patterns, generate truncated or antisense gene transcripts, alter splicing patterns, or result in premature polyadenylation of gene transcripts. Furthermore, the very high genomic copy numbers of these elements can lead to nonallelic homologous recombination events that produce gene deletions/ duplications and genome rearrangements, and can also lead to evolution of particular insertions or types of elements to have cellular functions through exaptation. Mobility of these elements occurs despite multiple epigenetic mechanisms to restrict their expression. While the potential for retrotransposons to significantly influence mammalian health and cellular functions is clear, substantial research efforts will be needed to fully elucidate the actual contributions of natural levels of mobility of endogenous elements to the health and development of humans and other mammals.

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Adenosine methylation as a molecular imprint defining the fate of RNA

Knuckles

Bühler

2018

FEBS Letters

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Multiple lines of evidence suggest the RNA modification N 6‐methyladonsine (m6A), which is installed in the nucleus cotranscriptionally and, thereafter, serves as a reversible chemical imprint that influences several steps of mRNA metabolism. This includes but is not limited to RNA folding, splicing, stability, transport and translation. In this Review we focus on the current view of the nuclear installation of m6A as well as the molecular players involved, the so called m6A writers. We also explore the effector proteins, or m6A readers, that decode the imprint in different cellular contexts and compartments, and ultimately, the way the modification influences the lifecycle of an RNA molecule. The wide evolutionary conservation of m6A and its critical role in physiology and disease warrants further studies into this burgeoning and exciting field.

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The Microprocessor controls the activity of mammalian retrotransposons

Cited by 105 publications

References 71 publications

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Consequences of ongoing retrotransposition in mammalian genomes

Adenosine methylation as a molecular imprint defining the fate of RNA

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