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Nuclear RNA surveillance: role of TRAMP in controlling exosome specificity

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Abstract The advent of high‐throughput sequencing technologies has revealed that pervasive transcription generates RNAs from nearly all regions of eukaryotic genomes. Normally, these transcripts undergo rapid degradation by a nuclear RNA surveillance system primarily featuring the RNA exosome. This multimeric protein complex plays a critical role in the efficient turnover and processing of a vast array of RNAs in the nucleus. Despite its initial discovery over a decade ago, important questions remain concerning the mechanisms that recruit and activate the nuclear exosome. Specificity and modulation of exosome activity requires additional protein cofactors, including the conserved TRAMP polyadenylation complex. Recent studies suggest that helicase and RNA‐binding subunits of TRAMP direct RNA substrates for polyadenylation, which enhances their degradation by Dis3/Rrp44 and Rrp6, the two exosome‐associated ribonucleases. These findings indicate that the exosome and TRAMP have evolved highly flexible functions that allow recognition of a wide range of RNA substrates. This flexibility provides the nuclear RNA surveillance system with the ability to regulate the levels of a broad range of coding and noncoding RNAs, which results in profound effects on gene expression, cellular development, gene silencing, and heterochromatin formation. This review summarizes recent findings on the nuclear RNA surveillance complexes, and speculates upon possible mechanisms for TRAMP‐mediated substrate recognition and exosome activation. WIREs RNA 2013, 4:217–231. doi: 10.1002/wrna.1155 This article is categorized under: RNA Processing > 3' End Processing RNA Processing > Processing of Small RNAs RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

Structural features of Air1 and Air2 and interaction with Trf4. (a) The protein sequences of Saccharomyces cerevisiae Air1 and Air2 were aligned using red font to indicate identical residues, and blue font to denote similar residues. Only the most highly conserved sequences are shown (amino acids 31‐204 of Air1, and 19‐193 of Air2). The numbered yellow boxes indicate the positions of the five zinc knuckle motifs, with the conserved CCHC residues highlighted in light blue boxes. The IWRxYxL motif is also specified. (b) Crystal structure of the catalytic and central domains of Trf4 (residues 161‐481; purple) bound to zinc knuckles 4 (ZK4) and 5 (ZK5) of Air2 (residues 122‐198; green).28 Zinc atoms are shown as red balls. The structure was modeled from Protein Data Base structure 3NYB using RCSB PDB Protein Workshop 4.0.

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Model of Air‐mediated inhibition of messenger ribonucleoprotein (mRNP) export. (a) Following accurate transcription, 3′ end processing, and polyadenylation, Npl3 binds properly processed mRNPs. Following methylation by Hmt1, Npl3 mediates export of the mRNP to the cytoplasm for translation. (b) If an mRNP is not properly processed, Air (likely in context of the TRAMP complex) is recruited to the aberrant mRNP and inhibits export by blocking Hmt1‐mediated methylation of Npl3. TRAMP recruits the exosome for degradation of mRNPs retained in the nucleus.

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Proposed mechanisms of TRAMP enhancement of exosomal degradation. (a) The priming model. Highly structured transcripts are modified by TRAMP, producing single‐stranded ends that are available for capture and subsequent degradation by Rrp6 and/or Dis3. These single‐stranded extensions are generated by the poly(A) polymerase activity of Trf4 or Trf5 (top), and/or by the 3′ → 5′ helicase activity of Mtr4 (bottom). (b) The kinetic or competitive model. Rapidly maturing RNAs are normally bound by 3′ end processing machinery. For simplicity, only the poly(A)‐binding proteins Hrb1, Nab2, and Pab1 are represented. For a complete review of 3′ end processing, see Ref 59. If the processing machinery encounters defects, however, the processing machinery will pause and eventually disassociate, exposing the 3′ end of the transcript for capture by TRAMP and the exosome. The inactive and unassociated TRAMP and 3′ end processing components are shown in gray. (c) The scaffold model. The 7s rRNA precursor is trimmed by Dis3 to within 30 nucleotides of its mature 3′ end. The Mtr4 arch domain then acts as an arm to transfer the 5.8s + 30 extended transcript to Rrp6, which trims the transcript to its final length. It is unclear if the Air proteins are required for this process and are therefore shown in gray.

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RNA Processing > Processing of Small RNAs
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Processing > 3′ End Processing

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