scholarly journals Activation and inhibition of nonsense-mediated mRNA decay controls the abundance of alternative polyadenylation products

2019 ◽  
Author(s):  
Aparna Kishor ◽  
Sarah E. Fritz ◽  
Nazmul Haque ◽  
Zhiyun Ge ◽  
Wenjing Yang ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Alternative Polyadenylation ◽  
Transcript Level ◽  
Untranslated Regions ◽  
Direct Modulation ◽  
Multiple Tumor ◽  
The Core ◽  
Polya Site ◽  
Nonsense Mediated Mrna Decay ◽  
Tumor Types

SUMMARYAlternative polyadenylation (APA) produces transcript 3’ untranslated regions (3’UTRs) with distinct sequences, lengths, stability, and functions. We show here that APA products include a class of cryptic nonsense-mediated mRNA decay (NMD) substrates with extended 3’UTRs that gene- or transcript-level analyses of NMD often fail to detect. Transcriptome-wide, the core NMD factor UPF1 preferentially recognizes long 3’UTR products of APA, leading to their systematic downregulation. Further, we find that many APA events consistently observed in multiple tumor types are controlled by NMD. Additionally, PTBP1, previously implicated in direct modulation of co-transcriptional polyA site choice, regulates the balance of short and long 3’UTR isoforms by inhibiting NMD. Our data suggest that PTBP1 binding near polyA sites can drive production of long 3’UTR APA products in the nucleus and/or protect them from decay in the cytoplasm. Together, our findings reveal a widespread role for NMD in shaping the outcomes of APA.

scholarly journals Activation and inhibition of nonsense-mediated mRNA decay control the abundance of alternative polyadenylation products

2020 ◽  
Author(s):  
Aparna Kishor ◽  
Sarah E Fritz ◽  
Nazmul Haque ◽  
Zhiyun Ge ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Alternative Polyadenylation ◽  
Transcript Level ◽  
Untranslated Regions ◽  
Multiple Tumor ◽  
The Core ◽  
Nonsense Mediated Mrna Decay ◽  
Tumor Types

Abstract Alternative polyadenylation (APA) produces transcript 3′ untranslated regions (3′UTRs) with distinct sequences, lengths, stabilities and functions. We show here that APA products include a class of cryptic nonsense-mediated mRNA decay (NMD) substrates with extended 3′UTRs that gene- or transcript-level analyses of NMD often fail to detect. Transcriptome-wide, the core NMD factor UPF1 preferentially recognizes long 3′UTR products of APA, leading to their systematic downregulation. Counteracting this mechanism, the multifunctional RNA-binding protein PTBP1 regulates the balance of short and long 3′UTR isoforms by inhibiting NMD, in addition to its previously described modulation of co-transcriptional polyadenylation (polyA) site choice. Further, we find that many transcripts with altered APA isoform abundance across multiple tumor types are controlled by NMD. Together, our findings reveal a widespread role for NMD in shaping the outcomes of APA.

scholarly journals A UPF1 variant drives conditional remodeling of nonsense-mediated mRNA decay

2021 ◽  
Author(s):  
Sarah E. Fritz ◽  
Soumya Ranganathan ◽  
J. Robert Hogg
Keyword(s):  
Gene Expression ◽  
Mrna Decay ◽  
Gene Expression Regulation ◽  
Translation Termination ◽  
Translational Repression ◽  
The Core ◽  
Human Genes ◽  
Rna Quality Control ◽  
Nonsense Mediated Mrna Decay

AbstractThe nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Due to the major role of NMD in RNA quality control and gene expression regulation, it is important to understand how the pathway responds to changing cellular conditions. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. UPF1LL associates more stably with potential NMD target mRNAs than the major UPF1SL isoform, expanding the scope of NMD to include many transcripts normally immune to the pathway. Unexpectedly, the enhanced persistence of UPF1LL on mRNAs supports induction of NMD in response to rare translation termination events. Thus, while canonical NMD is abolished by translational repression, UPF1LL activity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.

TMOD-30. NTRK2 SPLICE VARIANT, TRKB.T1, LINKS NEUROBIOLOGY, EMBRYONIC DEVELOPMENT, AND ONCOGENESIS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi222-vi222
Author(s):  
Siobhan Pattwell ◽  
Sonali Arora ◽  
Nicholas Nuechterlein ◽  
Michael Zager ◽  
Keith Loeb ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splice Variant ◽  
Transcript Level ◽  
Neurotrophin Receptor ◽  
Unique Role ◽  
Multiple Tumor ◽  
Oncology Research ◽  
Level Data ◽  
Wide Range ◽  
Tumor Types

Abstract Temporally regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and is highly expressed in a wide range of adult and pediatric tumors. Further, forced expression of TrkB.T1 causes multiple solid and non-solid tumors in mice in the context of tumor suppressor loss. These results highlight a unique role for the neurotrophin receptor splicing in development and oncogenesis and underscore the need for considering alternative splicing and transcript level data in neuroscience, developmental biology, and oncology research.

UPF1 P-body localization

2008 ◽  
Vol 36 (4) ◽  
pp. 698-700 ◽  
Author(s):  
Saverio Brogna ◽  
Preethi Ramanathan ◽  
Jikai Wen
Keyword(s):  
Mrna Decay ◽  
Translation Termination ◽  
Processing Bodies ◽  
Cytoplasmic Granules ◽  
P Bodies ◽  
The Core ◽  
Nonsense Mediated Mrna Decay ◽  
Premature Translation Termination

NMD (nonsense-mediated mRNA decay) is a mechanism that degrades transcripts containing PTCs (premature translation termination codons). NMD is a translation-associated process that is expected to take place throughout the cytoplasm. However, recent studies have indicated that the core NMD factors UPF1 (up-frameshift-1), UPF2 and UPF3 can associate with P-bodies (processing bodies), which are large cytoplasmic granules replete with proteins involved in general mRNA decay and related processes. It has been proposed that UPF1 directs PTC-containing mRNAs to P-bodies and triggers decay. Here, we discuss the link between P-bodies and NMD in view of recent studies that suggest that P-bodies are not required for NMD in Drosophila.

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