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

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          Abstract

          In this review, Zinder and Lima 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.

          Abstract

          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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          Most cited references122

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          Ribosome biogenesis in the yeast Saccharomyces cerevisiae.

          Ribosomes are highly conserved ribonucleoprotein nanomachines that translate information in the genome to create the proteome in all cells. In yeast these complex particles contain four RNAs (>5400 nucleotides) and 79 different proteins. During the past 25 years, studies in yeast have led the way to understanding how these molecules are assembled into ribosomes in vivo. Assembly begins with transcription of ribosomal RNA in the nucleolus, where the RNA then undergoes complex pathways of folding, coupled with nucleotide modification, removal of spacer sequences, and binding to ribosomal proteins. More than 200 assembly factors and 76 small nucleolar RNAs transiently associate with assembling ribosomes, to enable their accurate and efficient construction. Following export of preribosomes from the nucleus to the cytoplasm, they undergo final stages of maturation before entering the pool of functioning ribosomes. Elaborate mechanisms exist to monitor the formation of correct structural and functional neighborhoods within ribosomes and to destroy preribosomes that fail to assemble properly. Studies of yeast ribosome biogenesis provide useful models for ribosomopathies, diseases in humans that result from failure to properly assemble ribosomes.
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            RNA exosome depletion reveals transcription upstream of active human promoters.

            Studies have shown that the bulk of eukaryotic genomes is transcribed. Transcriptome maps are frequently updated, but low-abundant transcripts have probably gone unnoticed. To eliminate RNA degradation, we depleted the exonucleolytic RNA exosome from human cells and then subjected the RNA to tiling microarray analysis. This revealed a class of short, polyadenylated and highly unstable RNAs. These promoter upstream transcripts (PROMPTs) are produced approximately 0.5 to 2.5 kilobases upstream of active transcription start sites. PROMPT transcription occurs in both sense and antisense directions with respect to the downstream gene. In addition, it requires the presence of the gene promoter and is positively correlated with gene activity. We propose that PROMPT transcription is a common characteristic of RNA polymerase II (RNAPII) transcribed genes with a possible regulatory potential.
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              Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase.

              Since detection of an RNA molecule is the major criterion to define transcriptional activity, the fraction of the genome that is expressed is generally considered to parallel the complexity of the transcriptome. We show here that several supposedly silent intergenic regions in the genome of S. cerevisiae are actually transcribed by RNA polymerase II, suggesting that the expressed fraction of the genome is higher than anticipated. Surprisingly, however, RNAs originating from these regions are rapidly degraded by the combined action of the exosome and a new poly(A) polymerase activity that is defined by the Trf4 protein and one of two RNA binding proteins, Air1p or Air2p. We show that such a polyadenylation-assisted degradation mechanism is also responsible for the degradation of several Pol I and Pol III transcripts. Our data strongly support the existence of a posttranscriptional quality control mechanism limiting inappropriate expression of genetic information.
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                Author and article information

                Journal
                Genes Dev
                Genes Dev
                genesdev
                genesdev
                GAD
                Genes & Development
                Cold Spring Harbor Laboratory Press
                0890-9369
                1549-5477
                15 January 2017
                15 January 2017
                : 31
                : 2
                : 88-100
                Affiliations
                [1 ]Tri-Institutional Training Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA;
                [2 ]Structural Biology Program, Sloan Kettering Institute, New York, New York, 10065, USA;
                [3 ]Howard Hughes Medical Institute, New York, New York, 10065 USA
                Author notes
                Corresponding author: limac@ 123456mskcc.org
                Author information
                http://orcid.org/0000-0002-9163-6092
                Article
                8711660
                10.1101/gad.294769.116
                5322736
                28202538
                0214344a-6ffe-4c43-822a-b29b275c4e70
                © 2017 Zinder and Lima; Published by Cold Spring Harbor Laboratory Press

                This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

                History
                Page count
                Pages: 13
                Funding
                Funded by: National Institutes of Health/National Institute of General Medical Sciences http://dx.doi.org/10.13039/100000002
                Award ID: R01GM079196
                Award ID: R35GM118080
                Award ID: P30 CA008748
                Funded by: National Institutes of Health National Cancer Institute-Cancer Center http://dx.doi.org/10.13039/100000002
                Categories
                6
                Review

                3′ to 5′,rna degradation,rna exosome,rna processing,endoribonuclease,exoribonuclease,exosome

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