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1.
Mol Cell ; 68(6): 1095-1107.e5, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29272705

RESUMO

The RNAi pathway provides both innate immunity and efficient gene-knockdown tools in many eukaryotic species, but curiously not in zebrafish. We discovered that RNAi is less effective in zebrafish at least partly because Argonaute2-catalyzed mRNA slicing is impaired. This defect is due to two mutations that arose in an ancestor of most teleost fish, implying that most fish lack effective RNAi. Despite lacking efficient slicing activity, these fish have retained the ability to produce miR-451, a microRNA generated by a cleavage reaction analogous to slicing. This ability is due to a G-G mismatch within the fish miR-451 precursor, which substantially enhances its cleavage. An analogous G-G mismatch (or sometimes also a G-A mismatch) enhances target slicing, despite disrupting seed pairing important for target binding. These results provide a strategy for restoring RNAi to zebrafish and reveal unanticipated opposing effects of a seed mismatch with implications for mechanism and guide-RNA design.


Assuntos
Proteínas Argonautas/metabolismo , Pareamento Incorreto de Bases , MicroRNAs/metabolismo , Interferência de RNA , RNA Guia de Cinetoplastídeos/genética , RNA Mensageiro/genética , Peixe-Zebra/genética , Animais , Proteínas Argonautas/genética , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/genética , RNA Mensageiro/metabolismo , Complexo de Inativação Induzido por RNA/genética , Complexo de Inativação Induzido por RNA/metabolismo , Peixe-Zebra/fisiologia
2.
Nature ; 508(7494): 66-71, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24476825

RESUMO

Poly(A) tails enhance the stability and translation of most eukaryotic messenger RNAs, but difficulties in globally measuring poly(A)-tail lengths have impeded greater understanding of poly(A)-tail function. Here we describe poly(A)-tail length profiling by sequencing (PAL-seq) and apply it to measure tail lengths of millions of individual RNAs isolated from yeasts, cell lines, Arabidopsis thaliana leaves, mouse liver, and zebrafish and frog embryos. Poly(A)-tail lengths were conserved between orthologous mRNAs, with mRNAs encoding ribosomal proteins and other 'housekeeping' proteins tending to have shorter tails. As expected, tail lengths were coupled to translational efficiencies in early zebrafish and frog embryos. However, this strong coupling diminished at gastrulation and was absent in non-embryonic samples, indicating a rapid developmental switch in the nature of translational control. This switch complements an earlier switch to zygotic transcriptional control and explains why the predominant effect of microRNA-mediated deadenylation concurrently shifts from translational repression to mRNA destabilization.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Poli A/análise , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Animais , Arabidopsis/genética , Sequência de Bases , Linhagem Celular , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Gastrulação/genética , Humanos , Fígado/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Genéticos , Folhas de Planta/genética , Poli A/genética , Estabilidade de RNA/genética , RNA Mensageiro/metabolismo , Ribossomos/metabolismo , Análise de Sequência de RNA , Especificidade da Espécie , Transcrição Gênica , Xenopus/embriologia , Xenopus/genética , Leveduras/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Zigoto/metabolismo
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