Polypyrimidine tract binding protein 1 protects mRNAs from recognition by the nonsense-mediated mRNA decay pathway

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.DOI: http://dx.doi.org/10.7554/eLife.11155.001

Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways

“…Many transcripts with long 3 ′ UTRs or predicted uORFs are in fact known to escape NMD, and for some of them the NMD-protecting factors are known. For example, PTBP1 binding to the RNA stability element in Rous sarcoma virus protects the viral genomic RNA from NMD by preventing interaction of UPF1 with the 200-nt region downstream from the TC (Ge et al 2016). Furthermore, a high AU content within the first 200 nt downstream from the TC of several mRNAs with long 3 ′ UTRs has also been reported to confer resistance to NMD, but no trans-acting factor was identified (Toma et al 2015).…”

“…It is thought that UPF1 competes with PABPC1 for interacting with the eukaryotic release factor 3 (eRF3) (Singh et al 2008) and that an extended physical distance between the terminating ribosome and the poly(A) tail-associated PABPC1, which is a typical configuration of transcripts with uORFs, PTCs or long 3 ′ UTRs, increases the chance for UPF1 to win this competition and elicit NMD (Mühlemann and Jensen 2012). On the other hand, RNA-binding proteins that prevent UPF1 from accessing the mRNA just downstream from the TC can tilt the balance toward proper termination and inhibit NMD, as recently shown for Rous sarcoma virus (RSV) by polypyrimidine tract binding protein 1 (PTBP1) (Ge et al 2016).…”

RNA splicing factors as oncoproteins and tumour suppressors

“…However, if the ribosome stalls sufficiently upstream of an EJC, then NMD factors are recruited and activated 133,134 . Third, specific splicing factors including SRSF1, regulator of differentiation 1 (ROD1; also known as PTBP3) and PTB can enhance or repress NMD 135–137 .…”

Leveraging Rules of Nonsense-Mediated mRNA Decay for Genome Engineering and Personalized Medicine

“…As exemplified by “failsafe” NMD, also called 3′ UTR EJC-independent NMD, an exceptionally long (≥420 nt) 3′ UTR that is devoid of an EJC can trigger NMD, possibly because poly(A)-binding protein C1 (a known NMD antagonist) lies distant from the termination event (Figure 1D(vii)). Long 3′ UTRs may also harbor largely uncharacterized sequences situated immediately downstream of a termination codon that inhibit NMD (Toma et al, 2015) or, in some cases, CU-rich sequences that bind polypyrimidine tract-binding protein 1 and antagonize NMD (Ge et al, 2016). The 3′ UTR EJC-independent mode of NMD is less efficient at eliciting NMD than the 3′ UTR EJC-dependent mode; however, if the transcript in question derives from a splicing event, it may be possible to use CRISPR-Cas9 to convert it to an EJC-mediated NMD target by adhering to the 50–55 nt rule.…”