Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1

Cell Reports
Isabel AznarezAdrian R Krainer

Abstract

The splicing factor SRSF1 promotes nonsense-mediated mRNA decay (NMD), a quality control mechanism that degrades mRNAs with premature termination codons (PTCs). Here we show that transcript-bound SRSF1 increases the binding of NMD factor UPF1 to mRNAs while in, or associated with, the nucleus, bypassing UPF2 recruitment and promoting NMD. SRSF1 promotes NMD when positioned downstream of a PTC, which resembles the mode of action of exon junction complex (EJC) and NMD factors. Moreover, splicing and/or EJC deposition increase the effect of SRSF1 on NMD. Lastly, SRSF1 enhances NMD of PTC-containing endogenous transcripts that result from various events. Our findings reveal an alternative mechanism for UPF1 recruitment, uncovering an additional connection between splicing and NMD. SRSF1's role in the mRNA's journey from splicing to decay has broad implications for gene expression regulation and genetic diseases.

Citations

Aug 10, 2019·Clinical Genetics·Jameson PatakRobert R Lebel
Feb 1, 2020·Genes & Development·Mohammad Alinoor RahmanAdrian R Krainer
Apr 10, 2019·Nature Communications·Polina DenichenkoRotem Karni
Apr 18, 2019·Nature Reviews. Molecular Cell Biology·Tatsuaki KurosakiLynne E Maquat
May 28, 2019·Wiley Interdisciplinary Reviews. RNA·Aparna KishorJ Robert Hogg
Jul 9, 2020·Biomolecules·Daria Lavysh, Gabriele Neu-Yilik
Oct 4, 2020·Trends in Genetics : TIG·Zhongxia YiGuramrit Singh
Feb 9, 2021·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Rebecca E Wagner, Michaela Frye
Dec 17, 2020·International Journal of Molecular Sciences·Juan F García-Moreno, Luísa Romão
Mar 6, 2021·Signal Transduction and Targeted Therapy·Yuesheng LvYang Wang
May 1, 2021·Molecular Cancer·Gonçalo NogueiraLuísa Romão
Dec 24, 2021·Biochemical Society Transactions·Irena SliškovićMichaela Müller-McNicoll

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Methods Mentioned

BETA
co-immunoprecipitations
coIP
transfection
pull-down
flow cytometry
cross-linking immunoprecipitation
eCLIP

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