Interactions between the double-stranded RNA-binding proteins TRBP and PACT define the Medipal domain that mediates protein-protein interactions

Laraki, Ghislaine; Clerzius, Guerline; Daher, Aı̈cha; Melendez-Peña, Carlos E; Daniels, Sylvanne; Gatignol, Anne

doi:10.4161/rna.5.2.6069

Cited by 100 publications

(158 citation statements)

References 57 publications

(108 reference statements)

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“…Pervasive TARBP2 binding to intronic sequences implies that this dsRBP is present in the nucleus, which is further supported by a previous study that observed tagged TARBP2 in the nucleus of HeLa cells (Laraki et al, 2008). The Human Protein Atlas also provides immunofluorescence staining showing TARBP2 localized to the nucleoplasm of HeLa and MCF7 cells.…”

Section: Tarbp2 Binding Results In Increased Intron Retention and Dessupporting

confidence: 61%

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Fish

Nguyen

Zhang

et al. 2018

Preprint

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SUMMARYPost-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m 6 A RNA methylation machinery to its target transcripts, where deposition of m 6 A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression. RESEARCH HIGHLIGHTS• The RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleus• Nuclear TARBP2 recruits the methyltransferase complex to deposit m 6 A marks on its target transcripts • TARBP2 and m 6 A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.• Increased TARBP2 expression is associated with lung cancer and promotes lung cancer growth in vivo.• The transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.

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Section: Tarbp2 Binding Results In Increased Intron Retention and Dessupporting

confidence: 61%

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Fish

Nguyen

Zhang

et al. 2018

Preprint

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“…For example, four serine phosphorylation sites on TRBP alter processing of a set of pre-miRNAs related to cell growth when fully phosphorylated (Paroo et al 2009), although the mechanism of this effect is unknown. In addition, proteins other than Dicer, including PKR, PACT, and Merlin, may compete for TRBP binding (Daher et al 2001;Lee et al 2004;Laraki et al 2008). Other pre-miRNA binding proteins such as Lin28, hnRNPA1, and KHSRP (Heo et al 2008;Trabucchi et al 2009;Michlewski and Caceres 2010) also influence pre-miR processing in vivo and may change the effects of TRBP.…”

Section: Discussionmentioning

confidence: 99%

TRBP alters human precursor microRNA processing in vitro

Lee

Doudna

2012

RNA

127

125

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MicroRNAs play central roles in controlling gene expression in human cells. Sequencing data show that many miRNAs are produced at different levels and as multiple isoforms that can vary in length at their 59 or 39 ends, but the biogenesis and functional significance of these RNAs are largely unknown. We show here that the human trans-activation response (TAR) RNA binding protein (TRBP), a known molecular partner of the miRNA processing enzyme Dicer, changes the rates of pre-miRNA cleavage in an RNA-structure-specific manner. Furthermore, TRBP can trigger the generation of iso-miRNAs (isomiRs) that are longer than the canonical sequence by one nucleotide. We show that this change in miRNA processing site can alter guide strand selection, resulting in preferential silencing of a different mRNA target. These results implicate TRBP as a key regulator of miRNA processing and targeting in humans.

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“…It is possible that DRB4 dsRBD1 interacts with DCL4-DUF283, while dsRBD2 interacts with the C-terminal region of DCL4, and these two dsRBDs cooperatively facilitate the dsRNAcleaving activity of DCL4. There may be functional specialization between dsRBD1 and dsRBD2 of DRB4; such specialization is common for many eukaryotic dsRBPs (Hiraguri et al 2005;Laraki et al 2008;Qin et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Specific requirement of DRB4, a dsRNA-binding protein, for the in vitro dsRNA-cleaving activity of Arabidopsis Dicer-like 4

Fukudome¹,

Kanaya²,

Egami³

et al. 2011

RNA

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Arabidopsis thaliana Dicer-like 4 (DCL4) produces 21-nt small interfering RNAs from both endogenous and exogenous doublestranded RNAs (dsRNAs), and it interacts with DRB4, a dsRNA-binding protein, in vivo and in vitro. However, the role of DRB4 in DCL4 activity remains unclear because the dsRNA-cleaving activity of DCL4 has not been characterized biochemically. In this study, we biochemically characterize DCL4's Dicer activity and establish that DRB4 is required for this activity in vitro. Crude extracts from Arabidopsis seedlings cleave long dsRNAs into 21-nt small RNAs in a DCL4/DRB4-dependent manner. Immunoaffinity-purified DCL4 complexes produce 21-nt small RNAs from long dsRNA, and these complexes have biochemical properties similar to those of known Dicer family proteins. The DCL4 complexes purified from drb4-1 do not cleave dsRNA, and the addition of recombinant DRB4 to drb4-1 complexes specifically recovers the 21-nt small RNA generation. These results reveal that DCL4 requires DRB4 to cleave long dsRNA into 21-nt small RNAs in vitro. Amino acid substitutions in conserved dsRNA-binding domains (dsRBDs) of DRB4 impair three activities: binding to dsRNA, interacting with DCL4, and facilitating DCL4 activity. These observations indicate that the dsRBDs are critical for DRB4 function. Our biochemical approach and observations clearly show that DRB4 is specifically required for DCL4 activity in vitro.

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Interactions between the double-stranded RNA-binding proteins TRBP and PACT define the Medipal domain that mediates protein-protein interactions

Cited by 100 publications

References 57 publications

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

TRBP alters human precursor microRNA processing in vitro

Specific requirement of DRB4, a dsRNA-binding protein, for the in vitro dsRNA-cleaving activity of Arabidopsis Dicer-like 4

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