Activation and inhibition of nonsense-mediated mRNA decay control the abundance of alternative polyadenylation products. Issue 13 (15th June 2020)

• Record Type: Journal Article
• Authors: Kishor, Aparna; Fritz, Sarah E; Haque, Nazmul; Ge, Zhiyun; Tunc, Ilker; Yang, Wenjing; Zhu, Jun; Hogg, J Robert
• Is Part Of: Nucleic acids research. Volume 48:Issue 13(2020)
• Page Start: 7468
• Page End: 7482
• Publication Date: 2020-06-15
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa491
• Languages: English
• ISSNs: 0305-1048

Abstract

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.