The regulation and functions of the nuclear RNA exosome complex

Kilchert, Cornelia; Wittmann, Sina; Vasiljeva, Lidia

doi:10.1038/nrm.2015.15

Cited by 373 publications

(389 citation statements)

References 171 publications

(290 reference statements)

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“…This suggested that TARBP2 binds to pre-mRNAs and may function in the nucleus by influencing RNA processing and clearance. The major known pathway for RNA degradation in the nucleus involves the targeted destruction of incorrectly spliced transcripts by the RNA surveillance machinery (Kilchert et al, 2016). We hypothesized that TARBP2 may take advantage of this pathway by inhibiting efficient processing of its bound introns, resulting in nuclear retention and degradation of its target transcripts.…”

Section: Tarbp2 Binding Results In Increased Intron Retention and Desmentioning

confidence: 99%

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 Desmentioning

confidence: 99%

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Fish

Nguyen

Zhang

et al. 2018

Preprint

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“…Selective targeting has reported roles in diverse processes such as heterochromatic silencing, suppression of untimely meiosis in Schizosaccharomyces pombe, and viral defense (Harigaya et al 2006;Lee et al 2013;Aly et al 2016;Molleston et al 2016). Since targeting of RNA for degradation by the exosome based on RNA sequence elements was covered in a recent review (Kilchert et al 2016), we discuss alternative mechanisms of RNA targeting in this final section.…”

Section: Targeting Rnas To the Exosome And Associated Complexesmentioning

confidence: 99%

“…The eukaryotic RNA exosome is a conserved multisubunit protein complex that catalyzes 3 ′ -to-5 ′ processing or degradation of a vast array of different RNA substrates Kilchert et al 2016). Since its discovery as a key factor involved in 3 ′ processing of ribosomal RNAs (rRNAs) during ribosome biogenesis in budding yeast (Mitchell et al 1997), transcriptome-wide analyses in diverse eukaryotic model systems revealed that the RNA exosome contributes to the processing and/or degradation of nearly every class of RNA (Chekanova et al 2007;Gudipati et al 2012;Schneider et al 2012;Pefanis et al 2014).…”

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confidence: 99%

Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors

2017

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The eukaryotic RNA exosome is an essential and conserved protein complex that can degrade or process RNA substrates in the 3 ′ -to-5 ′ direction. Since its discovery nearly two decades ago, studies have focused on determining how the exosome, along with associated cofactors, achieves the demanding task of targeting particular RNAs for degradation and/or processing in both the nucleus and cytoplasm. In this review, we highlight recent advances that have illuminated roles for the RNA exosome and its cofactors in specific biological pathways, alongside studies that attempted to dissect these activities through structural and biochemical characterization of nuclear and cytoplasmic RNA exosome complexes.

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“…In the cytoplasm, the exosome participates in mRNA turnover and in surveillance pathways activated when ribosomes stall on aberrant mRNAs (Schaeffer et al 2011;Graille and Séraphin 2012;Shoemaker and Green 2012). In the nucleus, exosome-mediated degradation also eliminates unnecessary and defective RNAs (such as tRNAs or transcripts generated from pervasive transcription) and is involved in the biogenesis of structured RNAs [such as rRNAs and sn(o)RNAs] (Butler and Mitchell 2011;Sloan et al 2012;Kilchert et al 2016). The processing of rRNA is indeed a major function of this complex, which acts both at early nucleolar stages and at late nucleoplasmic stages of rRNA biogenesis (Thomson et al 2013;Henras et al 2015;Turowski and Tollervey 2015).…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the interaction of the nuclear exosome helicase Mtr4 with the preribosomal protein Nop53

Falk

Tants

Basquin

et al. 2017

RNA

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The nuclear exosome and the associated RNA helicase Mtr4 participate in the processing of several ribonucleoprotein particles (RNP), including the maturation of the large ribosomal subunit (60S). S. cerevisiae Mtr4 interacts directly with Nop53, a ribosomal biogenesis factor present in late pre-60S particles containing precursors of the 5.8S rRNA. The Mtr4-Nop53 interaction plays a pivotal role in the maturation of the 5.8S rRNA, providing a physical link between the nuclear exosome and the pre-60S RNP. An analogous interaction between Mtr4 and another ribosome biogenesis factor, Utp18, directs the exosome to an earlier preribosomal particle. Nop53 and Utp18 contain a similar Mtr4-binding motif known as the arch-interacting motif (AIM). Here, we report the 3.2 Å resolution crystal structure of S. cerevisiae Mtr4 bound to the interacting region of Nop53, revealing how the KOW domain of the helicase recognizes the AIM sequence of Nop53 with a network of hydrophobic and electrostatic interactions. The AIM-interacting residues are conserved in Mtr4 and are not present in the related cytoplasmic helicase Ski2, rationalizing the specificity and versatility of Mtr4 in the recognition of different AIM-containing proteins. Using nuclear magnetic resonance (NMR), we show that the KOW domain of Mtr4 can simultaneously bind an AIM-containing protein and a structured RNA at adjacent surfaces, suggesting how it can dock onto RNPs. The KOW domains of exosomeassociated helicases thus appear to have evolved from the KOW domains of ribosomal proteins and to function as RNPbinding modules in the context of the nuclear exosome.

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The regulation and functions of the nuclear RNA exosome complex

Cited by 373 publications

References 171 publications

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors

Structural insights into the interaction of the nuclear exosome helicase Mtr4 with the preribosomal protein Nop53

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