title: A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1.
abstract: 3'-untranslated regions (UTRs) specify post-transcriptional fates of mammalian messenger RNAs (mRNAs), yet knowledge of the underlying sequences and mechanisms is largely incomplete. Here, we identify two related novel 3' UTR motifs in mammals that specify transcript degradation. These motifs are interchangeable and active only within 3' UTRs, where they are often preferentially conserved; furthermore, they are found in hundreds of transcripts, many encoding regulatory proteins. We found that degradation occurs via mRNA deadenylation, mediated by the CCR4-NOT complex. We purified trans factors that recognize the motifs and identified heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2/B1, which are required for transcript degradation, acting in a previously unknown manner. We used RNA sequencing (RNA-seq) to confirm hnRNP A1 and A2/B1 motif-dependent roles genome-wide, profiling cells depleted of these factors singly and in combination. Interestingly, the motifs are most active within the distal portion of 3' UTRs, suggesting that their role in gene regulation can be modulated by alternative processing, resulting in shorter 3' UTRs.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA;
authors.forename: Rene
authors.initials: R
authors.lastname: Geissler
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA;
authors.forename: Alfred
authors.initials: A
authors.lastname: Simkin
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Doreen
authors.initials: D
authors.lastname: Floss
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA; Graduate Field of Genetics, Genomics, and Development, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fogarty
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA;
authors.forename: Andrew
authors.initials: A
authors.lastname: Grimson
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000072283:A549 Cells; D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000235:genetics*; D057809:HEK293 Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D020871:RNA Stability / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D059467:Transcriptome
chemical_list: D020413:3' Untranslated Regions; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B
keywords: 3′ UTR; CCR4–NOT deadenylase complex; cis-regulatory element; hnRNPs A2/B1 and A1; mRNA decay; post-transcriptional gene regulation