Secondary RNA structure and nucleotide specificity contribute to internal initiation mediated by the human tau 5′ leader

Veo, Bethany; Krushel, Leslie A.

doi:10.4161/rna.22181

Cited by 8 publications

(23 citation statements)

References 74 publications

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“…67,68 Separately, eukaryotic internal ribosome entry sites (IRESs) allow initiation of capindependent translation of mRNA. 69,70 IRES activity may be mediated by RNA structure, short sequence motifs in unstructured or structured regions that bind to IRES trans-acting factors (ITAFs), or base pairing with 18S ribosomal RNA (rRNA). 69,70 Additionally, sequence motifs within loop regions of IRESs may allow for RNA-RNA interactions and formation of secondary or tertiary structure essential for IRES function.…”

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

“…69,70 IRES activity may be mediated by RNA structure, short sequence motifs in unstructured or structured regions that bind to IRES trans-acting factors (ITAFs), or base pairing with 18S ribosomal RNA (rRNA). 69,70 Additionally, sequence motifs within loop regions of IRESs may allow for RNA-RNA interactions and formation of secondary or tertiary structure essential for IRES function. 69,70 The tau 5′ UTR contains a cis-regulatory internal ribosomal entry site (IRES) that contributed to 30% of the total translation of tau mRNA in luciferase assays.…”

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

“…69,70 Additionally, sequence motifs within loop regions of IRESs may allow for RNA-RNA interactions and formation of secondary or tertiary structure essential for IRES function. 69,70 The tau 5′ UTR contains a cis-regulatory internal ribosomal entry site (IRES) that contributed to 30% of the total translation of tau mRNA in luciferase assays. [67][68][69] Truncations to the IRES reduced or abolished IRES activity, suggesting that the entire sequence is required for IRES activity.…”

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

“…69,70 The tau 5′ UTR contains a cis-regulatory internal ribosomal entry site (IRES) that contributed to 30% of the total translation of tau mRNA in luciferase assays. [67][68][69] Truncations to the IRES reduced or abolished IRES activity, suggesting that the entire sequence is required for IRES activity. 69 A secondary structure model of the 240 nt IRES generated by SHAPE analysis yielded two domains.…”

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

“…[67][68][69] Truncations to the IRES reduced or abolished IRES activity, suggesting that the entire sequence is required for IRES activity. 69 A secondary structure model of the 240 nt IRES generated by SHAPE analysis yielded two domains. Among them, Domain I is a hairpin and Domain II is a multibranch loop.…”

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

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The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology

Chen

Moss

Spencer

et al. 2019

Preprint

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Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer's disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau's encoding RNA and their connection to disease pathology. Knowledge of RNA structure can provide insights into disease mechanisms and how to affect protein production for therapeutic benefit. Using computational methods based on thermodynamic stability and evolutionary conservation, we identified structures throughout the tau pre-mRNA, especially at exonintron junctions and within the 5′ and 3′ untranslated regions (UTRs). In particular, structures were identified at twenty exon-intron junctions. The 5′ UTR contains one structured region, which lies within a known internal ribosome entry site. The 3′ UTR contains eight structured regions, including one that contains a polyadenylation signal.A series of functional experiments were carried out to assess the effects of mutations associated with mis-regulation of alternative splicing of exon 10 and to identify regions of the 3′ UTR that contain cis-regulatory elements. These studies defined novel structural regions within the mRNA that affect stability and pre-mRNA splicing and may lead to new therapeutic targets for treating tau-associated diseases. ABBREVIATIONSAD, Alzheimer's disease; APA, alternative polyadenylation; APSI, average pairwise sequence identity; bp, base pair; DMEM, Dulbecco's Modified Eagle Medium; ED, ensemble diversity; FTDP-17, frontotemporal dementia with parkinsonism-17; htra2β1, transformer 2 beta homolog 1; IRES, internal ribosome entry site; ITAF, IRES trans-acting factor; MAFFT, Multiple Alignment using Fast Fourier Transform; MAPT, microtubule associated protein tau; MBD, microtubule binding domain; MFE, minimum free energy; miRNA, microRNA; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; MSTD, multiple system tauopathy with presenile dementia; ncRNA, noncoding RNA; nt, nucleotide; PD, Parkinson's disease; RNP, ribonucleoprotein;rRNA, ribosomal RNA; SCI, structure conservation index; SD, standard deviation; SF2, serine and arginine rich splicing factor 1, also known as SRSF1; SHAPE, selective 2′ hydroxyl acylation analyzed by primer extension; snRNA, small nuclear RNA; SRp30c, serine and arginine rich splicing factor 9, also known as SRSF9; SRp40, serine and arginine rich splicing factor 5, also known as SRSF5; SRp54, signal recognition particle 54; SRp55, serine and arginine rich splicing factor 6, also known as SRSF6; SVM, support vector machine; UTR, untranslated region

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Section: Structure Of the 5′ Utrmentioning

confidence: 99%

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

Section: Structure Of the 5′ Utrmentioning

confidence: 99%

See 3 more Smart Citations

The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology

Chen

Moss

Spencer

et al. 2019

Preprint

View full text Add to dashboard Cite

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Uncovering the impact of noncoding variants in neurodegenerative brain diseases

et al. 2022

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Neurodegenerative brain diseases (NBDs) are characterized by cognitive decline and movement impairments caused by neuronal loss in different brain regions. A large fraction of the genetic heritability of NBDs is not explained by the current known mutations. Genome-wide association studies identified novel diseaserisk loci, adding to the genetic basis of NBDs. Many of the associated variants reside in noncoding regions with distinct molecular functions. Genetic variation in these regions can alter functions and contribute to disease pathogenesis. Here, we discuss noncoding variants associated with NBDs. Methods for better functional interpretation of noncoding variation will expand our knowledge of the genetic architecture of NBDs and broaden the routes for therapeutic strategies. Noncoding elements in brain neurodegenerationNeurodegenerative brain diseases (NBDs) are neuropathologically characterized by protein aggregates that prompt progressive deterioration and loss of synaptic function. Pathological hallmarks differ between diseases. The clinical presentation depends on the affected brain regions and includes a range of cognitive and movement impairments (Box 1). Most studies so far have focused on the coding part to identify the genetic cause of NBDs. However, only a part of the heritability of NBDs is explained by coding mutations in genes causally linked with each disease [1-4]. Genome-wide association studies (GWAS) (see Glossary) have identified common genetic variants associated with various NBDs. Approximately 16-36% and 28% of the heritability of Parkinson's disease (PD) and of Alzheimer's disease (AD), respectively, can be explained by GWAS variants [5,6]. A considerable fraction of the variants is located in noncoding genome regions ). Functional modeling of variants has revealed disease-related mechanisms and explained part of the missing genetic etiology.

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MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration

Simone

Javad

Emmett

et al. 2021

Nature

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The human genome contains thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability, or translation of their overlapping genes 1,2 . We describe MAPT-AS1, a primate-conserved, brain-enriched NAT containing an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing with rRNA pairing to MAPT mRNA internal ribosome entry site (IRES) 3 . Tau, a neuronal intrinsically disordered protein (IDP), stabilises axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies 4 . MAPT mutations cause familial frontotemporal dementia (FTLD-tau), and common variation forming the MAPT H1 haplotype is a significant risk factor in many tauopathies 5 , and Parkinson's disease. Notably, expression of MAPT-AS1 or its minimal essential sequences including MIR reduces, whereas silenced MAPT-AS1 increases neuronal tau, and is correlated with tau pathology in human brain. Moreover, we identified hundreds additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration, and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. Collectively, we present the importance of MAPT-AS1 for tauopathies, while also uncovering a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs 6 , with particular relevance for proteostasis in neurodegeneration.

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Secondary RNA structure and nucleotide specificity contribute to internal initiation mediated by the human tau 5′ leader

Cited by 8 publications

References 74 publications

The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology

The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology

Uncovering the impact of noncoding variants in neurodegenerative brain diseases

MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration

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