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Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
Published on: August 9, 2019
Polypyrimidine tract binding protein 1 protects mRNAs from recognition by the nonsense-mediated mRNA decay pathway
Zhiyun Ge1, Bao Lin Quek2, Karen L Beemon2
1Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.
Abstract:
The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing long 3'UTRs to perform dual roles in mRNA quality control and gene expression regulation. However, expansion of vertebrate 3'UTR functions has required a physical expansion of 3'UTR lengths, complicating the process of detecting nonsense mutations. We show that the polypyrimidine tract binding protein 1 (PTBP1) shields specific retroviral and cellular transcripts from NMD. When bound near a stop codon, PTBP1 blocks the NMD protein UPF1 from binding 3'UTRs. PTBP1 can thus mark specific stop codons as genuine, preserving both the ability of NMD to accurately detect aberrant mRNAs and the capacity of long 3'UTRs to regulate gene expression. Illustrating the wide scope of this mechanism, we use RNA-seq and transcriptome-wide analysis of PTBP1 binding sites to show that many human mRNAs are protected by PTBP1 and that PTBP1 enrichment near stop codons correlates with 3'UTR length and resistance to NMD.
Insights
The polypyrimidine tract binding protein 1 (PTBP1) prevents the nonsense-mediated mRNA decay (NMD) pathway from degrading specific transcripts. This mechanism allows for longer 3'UTRs, crucial for gene regulation and accurate nonsense mutation detection.
Area of Science:
- Molecular Biology
- Gene Regulation
- RNA Metabolism
Background:
- The nonsense-mediated mRNA decay (NMD) pathway regulates gene expression by degrading aberrant mRNAs with premature stop codons.
- Long 3' untranslated regions (3'UTRs) are essential for complex gene regulation in vertebrates but pose challenges for NMD in detecting nonsense mutations.
Purpose of the Study:
- To investigate the mechanism by which specific transcripts are protected from NMD.
- To identify the role of polypyrimidine tract binding protein 1 (PTBP1) in modulating NMD activity and 3'UTR function.
Main Methods:
- RNA sequencing (RNA-seq) to analyze transcriptomes.
- Transcriptome-wide analysis of PTBP1 binding sites.
- Assessing PTBP1's effect on UPF1 binding to 3'UTRs near stop codons.
Main Results:
- PTBP1 binds to specific retroviral and cellular transcripts, shielding them from NMD.
- PTBP1 binding near a stop codon inhibits UPF1 binding to the 3'UTR, preventing mRNA degradation.
- PTBP1-mediated protection of mRNAs correlates with longer 3'UTR length and resistance to NMD in human transcripts.
Conclusions:
- PTBP1 acts as a crucial regulator, distinguishing genuine stop codons from nonsense mutations and preserving the regulatory capacity of long 3'UTRs.
- This mechanism ensures both mRNA quality control by NMD and sophisticated gene expression regulation.
- PTBP1 plays a significant role in protecting a substantial portion of human mRNAs from NMD.
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