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


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.

SUBMITTER: Kishor A 

PROVIDER: S-EPMC7367170 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Kishor Aparna A   Fritz Sarah E SE   Haque Nazmul N   Ge Zhiyun Z   Tunc Ilker I   Yang Wenjing W   Zhu Jun J   Hogg J Robert JR  

Nucleic acids research 20200701 13


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 t  ...[more]

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