Mechanisms of RNA export and nuclear retention

Khan, Muhammad Sufaid; Hou, Shuai; Chen, Mo; Lei, Hetian

doi:10.1002/wrna.1755

Cited by 15 publications

(8 citation statements)

References 138 publications

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“…Clearly, ORFs consisting of more than 100 codons in HML6-c14 transcripts that remain in the nucleus are not expected to be translated, as confirmed in the present study [ 24 , 25 ]. However, for ORFs shorter than that, we cannot discuss the possibility of protein translation until all analysis is complete.…”

Section: Discussionsupporting

confidence: 68%

“…These results beg the question of what role is served by HML6-c14 transcripts, either in the cytoplasm or nucleus. Recent reports suggest that splicing-defective mRNAs whose introns have not been removed or have not yet been spliced are retained in nuclear structures called nuclear speckles [ 24 , 25 , 26 ]. As far as we can see in Figure 3 a,b, the signal observed in the nucleus is relatively uniform, despite the presence of some densities, and does not appear to be concentrated in nuclear speckles, suggesting that an unknown mechanism might be responsible.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Expression Analysis Reveals HML6-c14 to Be an Attractive Research Target

Oda

2023

Biomolecules

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HML6-c14, a long terminal repeat (LTR)-type retrotransposon identified by expressed sequence tag (EST) database screening, was found to undergo RNA processing resembling that of placental tissue by in vitro expression analysis. Previous in situ hybridization studies using normal placental tissue showed that the transcript remained in the nucleus. However, among the transcripts forcedly expressed in cultured cells, the transcript that retained the 3.3 kb intron was observed in the nucleus, and a part of the spliced transcript was observed outside the nucleus. To verify whether this cytoplasmic transcript could be translated, we examined the coding potential of the open reading frame (ORF), consisting of 109 codons on the spliced transcript, along with two other putative ORFs detected in the intronic region. As a result, none of the ORF-derived products could be detected by Western blotting as fusion proteins tagged with the FLAG epitope, suggesting that HML6-c14 belongs to a group of long non-coding RNA (lncRNA) genes. Promoter analysis of the upstream 6.4 kb genomic region also suggested that the 5′-LTR itself potentially retains high promoter activity. Despite losing the ability to produce functional proteins, HML6-c14 continues to retain its transcriptional ability while converting to an lncRNA gene, which is an interesting subject for future research.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

In Vitro Expression Analysis Reveals HML6-c14 to Be an Attractive Research Target

Oda

2023

Biomolecules

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“…Other RNAs, in contrast, are degraded primarily in the nucleus, where nuclear transcriptome surveillance pathways capture unstable transcripts such as enhancer RNAs, products of pervasive transcription, and improperly processed transcripts [ 4 ]. Export of mRNA and non-coding RNA (tRNA, snoRNA, rRNA) occurs via different pathways (reviewed in [ 8 ]). Several adaptor proteins mediate the export of a mature mRNP through the nuclear pore complex [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Nuclear export is a limiting factor in eukaryotic mRNA metabolism

Müller,

Moos,

Baar

et al. 2024

PLoS Comput Biol

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The eukaryotic mRNA life cycle includes transcription, nuclear mRNA export and degradation. To quantify all these processes simultaneously, we perform thiol-linked alkylation after metabolic labeling of RNA with 4-thiouridine (4sU), followed by sequencing of RNA (SLAM-seq) in the nuclear and cytosolic compartments of human cancer cells. We develop a model that reliably quantifies mRNA-specific synthesis, nuclear export, and nuclear and cytosolic degradation rates on a genome-wide scale. We find that nuclear degradation of polyadenylated mRNA is negligible and nuclear mRNA export is slow, while cytosolic mRNA degradation is comparatively fast. Consequently, an mRNA molecule generally spends most of its life in the nucleus. We also observe large differences in the nuclear export rates of different 3’UTR transcript isoforms. Furthermore, we identify genes whose expression is abruptly induced upon metabolic labeling. These transcripts are exported substantially faster than average mRNAs, suggesting the existence of alternative export pathways. Our results highlight nuclear mRNA export as a limiting factor in mRNA metabolism and gene regulation.

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“…The nuclear export of proteins that contain nuclear export signals (NES) is typically mediated by exportin-1 (XPO1, also known as CRM1), and other members of the exportin family. The nuclear export of mRNA also requires NTF-mediated transport, and this involves proteins such as ALYREF, GLE1, and SRSF1 (Park et al, 2022 ; Khan et al, 2023 ). NTFs play crucial roles in regulating the transport of molecules between the nucleus and cytoplasm, ensuring the correct distribution of proteins and RNA within the cell.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS

McGoldrick,

Robertson

2023

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two adult-onset neurodegenerative diseases that are part of a common disease spectrum due to clinical, genetic, and pathological overlap. A prominent genetic factor contributing to both diseases is a hexanucleotide repeat expansion in a non-coding region of the C9orf72 gene. This mutation in C9orf72 leads to nuclear depletion and cytoplasmic aggregation of Tar DNA-RNA binding protein 43 (TDP-43). TDP-43 pathology is characteristic of the majority of ALS cases, irrespective of disease causation, and is present in ~50% of FTD cases. Defects in nucleocytoplasmic transport involving the nuclear pore complex, the Ran-GTPase cycle, and nuclear transport factors have been linked with the mislocalization of TDP-43. Here, we will explore and discuss the implications of these system abnormalities of nucleocytoplasmic transport in C9orf72-ALS/FTD, as well as in other forms of familial and sporadic ALS.

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Mechanisms of RNA export and nuclear retention

Cited by 15 publications

References 138 publications

In Vitro Expression Analysis Reveals HML6-c14 to Be an Attractive Research Target

In Vitro Expression Analysis Reveals HML6-c14 to Be an Attractive Research Target

Nuclear export is a limiting factor in eukaryotic mRNA metabolism

Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS

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