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Nuclear sorting of RNA

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Abstract The majority of the mammalian genome is transcribed by RNA polymerase II, yielding a vast amount of noncoding RNA (ncRNA) in addition to the standard production of mRNA. The typical nuclear biogenesis of mRNA relies on the tightly controlled coupling of co‐ and post‐transcriptional processing events, which ultimately results in the export of transcripts into the cytoplasm. These processes are subject to surveillance by nuclear RNA decay pathways to prevent the export of aberrant, or otherwise “non‐optimal,” transcripts. However, unlike mRNA, many long ncRNAs are nuclear retained and those that maintain enduring functions must employ precautions to evade decay. Proper sorting and localization of RNA is therefore an essential activity in eukaryotic cells and the formation of ribonucleoprotein complexes during early stages of RNA synthesis is central to deciding such transcript fate. This review details our current understanding of the pathways and factors that direct RNAs towards a particular destiny and how transcripts combat the adverse conditions of the nucleus. This article is categorized under: RNA Export and Localization > Nuclear Export/Import RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Cap binding complex (CBC) associating factors provide a first step in defining Pol II transcript fate. The formation of CBC‐containing RNPs is dynamic due to mutually exclusive interactions of various adaptors. (a) Nascent CBC‐bound RNAs are targeted by the negative elongation factor (NELF) complex, involved in early transcriptional pausing. As transcription enters the elongation stage, NELF is replaced by ARS2 to form the CBCA complex. (b) The CBCA complex provides a platform for subsequent competitive interactions of ALYREF, PHAX, FLASH, and ZC3H18, hereby initializing the creation of RNP identity. (c) ARS2 in turn interacts with RNP adaptors that connect to downstream productive or destructive pathways: (i) the TREX component ALYREF promotes nuclear export of mRNAs via the NXF1 export receptor; (ii) smaller RNAs, such as snRNAs and independently transcribed snoRNAs, are bound by CBCA and PHAX, forming the CBCAP complex, which connects these transcripts to their respective export and localization pathways; (iii) downstream processing of RDH mRNAs is facilitated through association of FLASH to ARS2, and (iv) pervasively transcribed transcripts, such as eRNAs, PROMPTs and many lncRNAs, are targeted for nuclear decay via the interaction of the CBCA complex with ZC3H18, which in turn recruits nuclear exosome targeting complexes NEXT and/or PAXT (see Figure for further detail)
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Nuclear retention on chromatin. Several lncRNAs are actively retained in the nucleus by sequestration on chromatin. This is exemplified by the well‐characterized lncRNAs XIST and FIRRE. (a) While XIST is processed analogous to mRNAs, it is actively anchored in the nucleus through interactions with heterogeneous nuclear ribonucleoproteins (hnRNP), such as hnRNPU, which mediates RNA:chromatin interactions. XIST further recruits epigenetic factors such as PRC2 and histone deacetylases (HDACs) to aid in silencing the X‐chromosome. (b) The FIRRE lncRNA has been shown to mediate interchromosomal interactions between the host X chromosome and other genomic locations. An identified repeating domain, acting as a retention element, is involved in binding to hnRNPU and mediating the interaction with chromatin
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Escaping decay in subnuclear compartments. For continued survival in the nucleus, some RNAs are sequestered into RNP aggregates such as nuclear speckles and paraspeckles as exemplified by MALAT1 and NEAT1, respectively. (Left) NEAT1 harbors a triple helical structure at its 3′ end and engages co‐transcriptionally with paraspeckle factors, such as DBHS protein family members. NEAT1 itself plays an integral role in the structure and maintenance of paraspeckles, which are subsequently involved in the retention of other RNAs. (Right) MALAT1 also possesses a protective triple helical 3′‐end. Two identified sequence elements are crucial for the retention of MALAT1 in the nucleus and bind to the nuclear speckle protein RNPS1. MALAT1 is not intrinsic to the structure of nuclear speckles but is proposed to function in the recruitment of mRNA processing factors to these subnuclear compartments
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Nuclear exosome targeting complexes. The ribonucleolytic nuclear exosome complex is regulated by interactions with distinct targeting and inhibitory complexes/factors. The core exosome (EXO9) forms a catalytically inert barrel structure and associates with the exonuclease RRP6 and the exo/endonuclease DIS3 (EXO11) along with the cofactors RRP47 and MPP6 (EXO13). Transcripts are targeted to the exosome via adaptor complexes, forming mutually exclusive interactions with the RNA helicase MTR4. In the nucleoplasm, these include the nuclear exosome targeting (NEXT) complex (MTR4:ZCCHC8:RBM7) and the polyA exosome targeting (PAXT) connection (MTR4:ZFC3H1:PABPN1). Both NEXT and PAXT can be physically connected to capped RNAs via the CBCA adaptor protein ZC3H18. The TRAMP adaptor complex (MTR4:ZCCHC7:PAPD5) is restricted to the nucleolus and is predominantly engaged with the exosome in rRNA processing. To dampen RNA decay in nuclear speckles, sites of productive mRNA processing and export factors, MTR4 is bound by the NRDE2 protein. This locks MTR4 in a closed conformation and blocks its interactions with the CBCA and EXO13
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Defense against exonucleases. To survive the harsh environment of surveying nuclear exonucleases, RNAs require protective elements at their 5′ and 3′‐ends. (a) 5′‐end protection. Initiating nascent RNAs have a 5′ triphosphate, which is incompatible with 5′–3′ exonucleolytic decay. This 5′‐end is matured with a m7G cap, which is subsequently bound by the cap binding complex (CBC), providing additional protection. (b) 3′‐end protection. Most mRNAs are protected at their 3′‐ends by the polyA tail and its bound polyA binding proteins (PABPs). Nonpolyadenylated transcripts, such as replication dependent histone (RDH) RNAs, harbor distinct stem loop structures bound by the stem loop binding protein (SLBP) to provide transcript stability. Some nuclear retained lncRNAs, such as NEAT1 and MALAT1, form unique triple helical 3′‐ends, owing to genomic encoded A‐ and U‐rich stretches, which are inaccessible for 3′–5′ exonucleases. Small nucleolar RNAs (snoRNAs) are tightly bound into snoRNP structures, shielding their 3′ ends. Small nuclear RNAs (snRNAs) are bound by a group of Sm proteins in the cytoplasm. These constitute a heptameric ring complex that forms on the RNA before reimport to the nucleus
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Cleavage and termination complexes. The recruitment and action of distinct cleavage and 3′‐end processing complexes is influenced by cis‐elements within the 3′‐end of the nascent RNA. (i) Canonical mRNAs utilize the cleavage and polyadenylation machinery, predominantly guided by the presence of a polyadenylation signal (PAS), aided by an upstream auxiliary element (UAE) and downstream element (DSE). Together, these recruit the cleavage and polyadenylation factor (CPSF), cleavage factors I and II (CFI, CFII) and cleavage stimulatory factor (CstF). RNA cleavage is carried out by CPSF73 and subsequently transcripts are polyadenylated by PAP. (ii) RDH mRNAs contain conserved stem loop sequences and histone downstream elements (HDEs), which are bound by the stem loop binding protein (SLBP) and the U7‐snRNP, respectively. Cleavage is also carried out by CPSF73 and the resulting 3′ end remains bound to SLBP throughout downstream processing. (iii) snRNAs and a small number of independently transcribed snoRNAs are processed by the integrator (INT) complex. This is recognized by conserved stem loop and 3′ box motifs in the nascent transcript. Cleavage is carried out by the CPSF73 homolog INTS11. (iv) The 3′ end of MALAT1 and NEAT1 transcripts are processed by tRNA biogenesis factors due to presence of an RNaseP sequence element. These RNAs form an unusual triple helical structure owing to complementary U‐ and A‐rich sequences upstream of the cleavage site
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Export and Localization > Nuclear Export/Import

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