A Nuclear Export Block Triggers the Decay of Newly Synthesized Polyadenylated RNA

Tudek, Agnieszka; Schmid, Manfred; Makaras, Marius; Barrass, J. David; Beggs, Jean D.; Jensen, Torben Heick

doi:10.1016/j.celrep.2018.07.103

Cited by 42 publications

(56 citation statements)

References 59 publications

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“…We speculate that an abundant number of introns might increase RNA nuclear residence time and therefore require NCBP3 to fend off nuclear decay activities (as exemplified by its competition with ZC3H18), while providing additional export capacity. As shown previously in both yeast and human cells, efficient nuclear export is required to evade nuclear decay by the RNA exosome (29,64,65). Loss of NCBP3 might therefore de-stabilize these multiexonic transcripts dually due to their slowed nuclear export and enhanced turnover (Fig.…”

Section: Discussionsupporting

confidence: 63%

NCBP3 is a productive mRNP component

Dou

Barbosa

Jiang

et al. 2020

Preprint

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AbstractThe nuclear Cap Binding Complex (CBC), consisting of Nuclear Cap Binding Protein 1 (NCBP1) and 2 (NCBP2), associates with the nascent 5’cap of RNA polymerase II transcripts and impacts RNA fate decisions. Recently, the C17orf85 protein, also called NCBP3, was suggested to form an alternative CBC by replacing NCBP2. However, applying protein-protein interaction screening of NCBP1, 2 and 3, we find that the interaction profile of NCBP3 is distinct. Whereas NCBP1 and 2 identify known CBC interactors, NCBP3 primarily interacts with components of the Exon Junction Complex (EJC) and the TRanscription and EXport (TREX) complex. NCBP3-EJC association in vitro and in vivo requires EJC core integrity and the in vivo RNA binding profiles of EJC and NCBP3 overlap. We further show that NCBP3 competes with the RNA degradation factor ZC3H18 for binding CBC-bound transcripts, and that NCBP3 positively impacts the nuclear export of polyadenylated RNAs and the expression of large multi-exonic transcripts. Collectively, our results place NCBP3 with the EJC and TREX complexes in supporting the productive fate of mRNA.

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Section: Discussionsupporting

confidence: 63%

NCBP3 is a productive mRNP component

Dou

Barbosa

Jiang

et al. 2020

Preprint

Self Cite

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“…Critically, in the absence of nuclear Nab2, nuclear mRNA is rapidly degraded by the RNA exosome . Moreover, if nuclear export of mature mRNPs is blocked, newly synthesized mRNA transcripts are quickly degraded and this has been proposed to be because of the reduced availability of Nab2, which is unavailable because it is bound to the older previously generated transcripts …”

Section: Scnab2 Regulation Of Poly(a) Tail Lengthmentioning

confidence: 99%

“…56 Moreover, if nuclear export of mature mRNPs is blocked, newly synthesized mRNA transcripts are quickly degraded and this has been proposed to be because of the reduced availability of Nab2, which is unavailable because it is bound to the older previously generated transcripts. 57 Overall, extensive analyses of ScNab2 Zn finger variants has indicated that the ScNab2 ZnF567 interaction with polyadenosine RNA plays a central role in the regulation of poly(A) tail length and mRNA compaction in S. cerevisiae. In this context, the observation that the loss of DmNab2 in Drosophila and ZC3H14 in mice and humans results in longer poly(A) tails 12,13,55 suggests that DmNab2 ZnF123 and ZC3H14 ZnF123, which are most similar to ScNab2 ZnF567 [ Fig.…”

Section: Scnab2 Regulation Of Poly(a) Tail Lengthmentioning

confidence: 99%

Structure–function relationships in the Nab2 polyadenosine‐RNA binding Zn finger protein family

2019

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The poly(A) RNA binding Zn finger ribonucleoprotein Nab2 functions to control the length of 3′ poly(A) tails in Saccharomyces cerevisiae as well as contributing to the integration of the nuclear export of mature mRNA with preceding steps in the nuclear phase of the gene expression pathway. Nab2 is constructed from an N‐terminal PWI‐fold domain, followed by QQQP and RGG motifs and then seven CCCH Zn fingers. The nuclear pore‐associated proteins Gfd1 and Mlp1 bind to opposite sides of the Nab2 N‐terminal domain and function in the nuclear export of mRNA, whereas the Zn fingers, especially fingers 5–7, bind to A‐rich regions of mature transcripts and function to regulate poly(A) tail length as well as mRNA compaction prior to nuclear export. Nab2 Zn fingers 5–7 have a defined spatial arrangement, with fingers 5 and 7 arranged on one side of the cluster and finger 6 on the other side. This spatial arrangement facilitates the dimerization of Nab2 when bound to adenine‐rich RNAs and regulates both the termination of 3′ polyadenylation and transcript compaction. Nab2 also functions to coordinate steps in the nuclear phase of the gene expression pathway, such as splicing and polyadenylation, with the generation of mature mRNA and its nuclear export. Nab2 orthologues in higher Eukaryotes have similar domain structures and play roles associated with the regulation of splicing and polyadenylation. Importantly, mutations in the gene encoding the human Nab2 orthologue ZC3H14 and cause intellectual disability.

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“…Inactivation of Mex67 leads to nuclear accumulation of mRNA ( Segref et al, 1997 ; Santos-Rosa et al, 1998 ). In addition, in the absence of Mex67, poly-A + RNA appears to be extremely unstable, which was attributed to untimely RNA decay due to the export block ( Tudek et al, 2018 ). Notably, Mex67 is also somehow implicated in the cytoplasmic export of Xpo1-transported cargoes, such as snRNA, rRNA, and tRNA, raising a question of why these RNA species require two export receptors ( Yao et al, 2007 ; Faza et al, 2012 ; Chatterjee et al, 2017 ; Becker et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Telomerase biogenesis requires a novel Mex67 function and a cytoplasmic association with the Sm7 complex

Vasianovich

Bajon

Wellinger

2020

eLife

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The templating RNA is the core of the telomerase reverse transcriptase. In Saccharomyces cerevisiae, the complex life cycle and maturation of telomerase includes a cytoplasmic stage. However, timing and reason for this cytoplasmic passage are poorly understood. Here, we use inducible RNA tagging experiments to show that immediately after transcription, newly synthesized telomerase RNAs undergo one round of nucleo-cytoplasmic shuttling. Their export depends entirely on Crm1/Xpo1, whereas re-import is mediated by Kap122 plus redundant, kinetically less efficient import pathways. Strikingly, Mex67 is essential to stabilize newly transcribed RNA before Xpo1-mediated nuclear export. The results further show that the Sm7 complex associates with and stabilizes the telomerase RNA in the cytoplasm and promotes its nuclear re-import. Remarkably, after this cytoplasmic passage, the nuclear stability of telomerase RNA no longer depends on Mex67. These results underscore the utility of inducible RNA tagging and challenge current models of telomerase maturation.

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A Nuclear Export Block Triggers the Decay of Newly Synthesized Polyadenylated RNA

Cited by 42 publications

References 59 publications

NCBP3 is a productive mRNP component

NCBP3 is a productive mRNP component

Structure–function relationships in the Nab2 polyadenosine‐RNA binding Zn finger protein family

Telomerase biogenesis requires a novel Mex67 function and a cytoplasmic association with the Sm7 complex

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