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PMID: 31522989 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A Complex of U1 snRNP with Cleavage and Polyadenylation Factors Controls Telescripting, Regulating mRNA Transcription in Human Cells.

Molecular cell ·Vol. 76 ·No. 4 ·2019-00-21 ·Pages 590-599.e4

So BR, Di C, Cai Z, Venters CC, Guo J, Oh JM, Arai C, Dreyfuss G

Abstract

Full-length transcription in the majority of human genes depends on U1 snRNP (U1) to co-transcriptionally suppress transcription-terminating premature 3' end cleavage and polyadenylation (PCPA) from cryptic polyadenylation signals (PASs) in introns. However, the mechanism of this U1 activity, termed telescripting, is unknown. Here, we captured a complex, comprising U1 and CPA factors (U1-CPAFs), that binds intronic PASs and suppresses PCPA. U1-CPAFs are distinct from U1-spliceosomal complexes; they include CPA's three main subunits, CFIm, CPSF, and CstF; lack essential splicing factors; and associate with transcription elongation and mRNA export complexes. Telescripting requires U1:pre-mRNA base-pairing, which can be disrupted by U1 antisense oligonucleotide (U1 AMO), triggering PCPA. U1 AMO remodels U1-CPAFs, revealing changes, including recruitment of CPA-stimulating factors, that explain U1-CPAFs' switch from repressive to activated states. Our findings outline this U1 telescripting mechanism and demonstrate U1's unique role as central regulator of pre-mRNA processing and transcription.

Keywords
-end processing U1 snRNP cleavage and polyadenylation mRNA 3ʹ telescripting transcription elongation transcription termination
MeSH Terms
3' Untranslated Regions Active Transport, Cell Nucleus Binding Sites Cell Nucleus/genetics,metabolism Cleavage And Polyadenylation Specificity Factor/genetics,metabolism Cleavage Stimulation Factor/genetics,metabolism HeLa Cells Humans Multiprotein Complexes Poly A/metabolism Protein Binding RNA Cleavage RNA Precursors/biosynthesis,genetics RNA, Messenger/biosynthesis,genetics Ribonucleoprotein, U1 Small Nuclear/genetics,metabolism Transcription, Genetic
Chemicals
3' Untranslated Regions Cleavage And Polyadenylation Specificity Factor Cleavage Stimulation Factor Multiprotein Complexes RNA Precursors RNA, Messenger Ribonucleoprotein, U1 Small Nuclear Poly A
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
So Byung Ran
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Di Chao
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Cai Zhiqiang
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Venters Christopher C
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Guo Jiannan
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Oh Jung-Min
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Arai Chie
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Dreyfuss Gideon
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. Electronic address: gdreyfuss@hhmi.upenn.edu.
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2019.08.007
Email
gdreyfuss@hhmi.upenn.edu
Published
2019-00-21
Epub
2019-00-12
Pages
590-599.e4
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC6874754
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · R01 GM112923 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2019.08.007 PMC Full Text View journal details
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