Emerging Roles of RNA 3′-end Cleavage and Polyadenylation in Pathogenesis, Diagnosis and Therapy of Human Disorders

Nourse, Jamie P.; Spada, Stefano; Danckwardt, Sven

doi:10.3390/biom10060915

Cited by 55 publications

(63 citation statements)

References 415 publications

(553 reference statements)

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“…Further support for the regulatory importance of the F11 gene 3'UTR comes from the observation that while the 3'UTR of F12 is relatively short (~150 nucleotides), that of F11 spans over ~1000 nucleotides, and as described previously F11 3'UTR SNPs are associated with plasma FXI activity and risk of venous thrombosis. Additionally, the F11 3'UTR is under control of alternative polyadenylation, which is consistent with increased regulation of gene expression and is associated with several diseases (Nourse, Spada, & Danckwardt, 2020). In addition to the high number of miRNAs, using RNA affinity pull-downs coupled to mass spectrometry, we identify here that the F11 3'UTR also binds numerous RNA binding proteins (RBPs) in close proximity to, and sometimes even in the direct target region of miRNAs ( Figure 3B-C).…”

Section: Factor XI Mirna As a Novel Anticoagulant Therapy Targeting Amentioning

confidence: 68%

A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

Nourse

Danckwardt

2018

Preprint

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The treatment and prevention of thrombosis is currently under a period of rapid change with the replacement of traditional anticoagulant vitamin K antagonists with direct oral anticoagulants (DOACs), which specifically target factors FXa or FIIa.Nevertheless therapeutic targeting of blood coagulation is an inherently difficult task as it interferes with the delicate balance of pro-and anticoagulant activities. Although anticoagulants are employed in millions of thrombophilic patients worldwide each year, for a growing population with comorbidities who exhibit an increased risk of bleeding with DOAC treatment satisfying therapeutic options are still lacking and the quest for novel therapeutics continues.Recently the targeting of factors FXI and FXII have emerged as new therapeutic strategies. As these factors play an important roles in thrombosis, however are more or less functionally dispensable for hemostasis, they may potentially overcoming the functional obstacle of treating or preventing thrombosis without affecting hemostasis.A key question in following up this approach is which of these two factors is likely to be the more reliable target? Here we present and discuss a hitherto unrecognized rationale for the therapeutic targeting of FXI. This is based on mimicking endogenous FXI gene expression control by therapeutic delivery of miRNA mimics.Studies are urgently needed to test this therapeutic principle in a clinical setting. This is particularly applicable in hemostaseology where monitoring of therapeutic effects remains a daily routine and thus assessment of the efficacy and safety of such therapeutic components could be simply implemented ushering in a novel therapeutic era with broad applicability.

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Section: Factor XI Mirna As a Novel Anticoagulant Therapy Targeting Amentioning

confidence: 68%

A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

Nourse

Danckwardt

2018

Preprint

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“…While the locale of the YGCAUGCR m6A motif may imply a role for the m6A system in 3’-end formation, the near complete purification of the cleavage and polyadenylation machinery along with the only two YTH domain-containing proteins, strongly positions the m6A system as a foundational piece driving this crucial process. The functions and individual constituents of the various cleavage and polyadenylation machinery are reviewed elsewhere (32, 43, 45); however, they can be broken down into cleavage and polyadenylation specificity factors (CPSF), cleavage stimulation factors (CSTF), and cleavage factors I and II (CFs).…”

Section: Discussionmentioning

confidence: 99%

m6A RNA methylation facilitates pre-mRNA 3’-end formation and is essential for viability ofToxoplasma gondii

Holmes

Padgett

Bastos

et al. 2021

Preprint

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Toxoplasma gondii is an obligate intracellular parasite that can cause serious opportunistic disease in the immunocompromised or through congenital infection. To progress through its life cycle, Toxoplasma relies on multiple layers of gene regulation that includes an array of transcription and epigenetic factors. Over the last decade, the modification of mRNA has emerged as another important layer of gene regulation called epitranscriptomics. Here, we report that epitranscriptomics machinery exists in Toxoplasma, namely the methylation of adenosines (m6A) in mRNA transcripts. We identified novel components of the m6A methyltransferase complex and determined the distribution of m6A marks within the parasite transcriptome. m6A mapping revealed the modification to be preferentially located near the 3’-boundary of mRNAs within the consensus sequence, YGCAUGCR. Knockdown of the m6A writer enzyme METTL3 resulted in diminished m6A marks, loss of a target transcript, and a complete arrest of parasite replication. Furthermore, we examined the two proteins in Toxoplasma that possess YTH domains, which bind m6A marks, and showed them to be integral members of the cleavage and polyadenylation machinery that catalyzes the 3’-end processing of pre-mRNAs. Together, these findings establish that the m6A epitranscriptome is essential for parasite viability by contributing to the processing of mRNA 3’-ends.Author SummaryToxoplasma gondii is a parasite of medical importance that causes disease upon immuno-suppression. Uncovering essential pathways that the parasite uses for its basic biological processes may reveal opportunities for new anti-parasitic drug therapies. Here, we describe the machinery that Toxoplasma uses to modify specific adenosine residues within its messenger RNAs (mRNA) by N6-adenosine methylation (m6A). We discovered that m6A mRNA methylation is prevalent in multiple stages of the parasite life cycle and is required for parasite replication. We also establish that m6A plays a major role in the proper maturation of mRNA. Two proteins that bind m6A modifications on mRNA associate with factors responsible for the cleavage and final processing steps of mRNA maturation. Since all of the machinery is conserved from plants to Toxoplasma and other related parasites, we propose that this system operates similarly in these organisms.

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“…Nuclear export of mRNA is an essential process in eukaryotic gene expression. Immediately after initiation of transcription, mRNA binds to various proteins to form an mRNA–protein complex (messenger ribonucleoprotein: mRNP) [ 35 , 36 ]. The mRNA precursor transcribed in the nucleus matures through complex processing such as capping, splicing, and 3′-terminal cleavage and poly(A) chain addition (cleavage and polyadenylation: CPA) [ 37 ].…”

Section: The Role Of the Nuclear Envelope Nuclear Pore Complexes Anmentioning

confidence: 99%

Nuclear Envelope and Nuclear Pore Complexes in Neurodegenerative Diseases—New Perspectives for Therapeutic Interventions

et al. 2020

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Transport of proteins, transcription factors, and other signaling molecules between the nucleus and cytoplasm is necessary for signal transduction. The study of these transport phenomena is particularly challenging in neurons because of their highly polarized structure. The bidirectional exchange of molecular cargoes across the nuclear envelope (NE) occurs through nuclear pore complexes (NPCs), which are aqueous channels embedded in the nuclear envelope. The NE and NPCs regulate nuclear transport but are also emerging as relevant regulators of chromatin organization and gene expression. The alterations in nuclear transport are regularly identified in affected neurons associated with human neurodegenerative diseases. This review presents insights into the roles played by nuclear transport defects in neurodegenerative disease, focusing primarily on NE proteins and NPCs. The subcellular mislocalization of proteins might be a very desirable means of therapeutic intervention in neurodegenerative disorders.

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Emerging Roles of RNA 3′-end Cleavage and Polyadenylation in Pathogenesis, Diagnosis and Therapy of Human Disorders

Cited by 55 publications

References 415 publications

A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

m6A RNA methylation facilitates pre-mRNA 3’-end formation and is essential for viability ofToxoplasma gondii

Nuclear Envelope and Nuclear Pore Complexes in Neurodegenerative Diseases—New Perspectives for Therapeutic Interventions

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