SAM68 interaction with U1A modulates U1 snRNP recruitment and regulates mTor pre-mRNA splicing
Open Access
- 15 February 2019
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 47 (8), 4181-4197
- https://doi.org/10.1093/nar/gkz099
Abstract
Src associated in mitosis (SAM68) plays major roles in regulating RNA processing events, such as alternative splicing and mRNA translation, implicated in several developmental processes. It was previously shown that SAM68 regulates the alternative splicing of the mechanistic target of rapamycin (mTor), but the mechanism regulating this process remains elusive. Here, we report that SAM68 interacts with U1 small nuclear ribonucleoprotein (U1 snRNP) to promote splicing at the 5' splice site in intron 5 of mTor. We also show that this direct interaction is mediated through U1A, a core-component of U1snRNP. SAM68 was found to bind the RRM1 domain of U1A through its C-terminal tyrosine rich region (YY domain). Deletion of the U1A-SAM68 interaction domain or mutation in SAM68-binding sites in intron 5 of mTor abrogates U1A recruitment and 5' splice site recognition by the U1 snRNP, leading to premature intron 5 termination and polyadenylation. Taken together, our results provide the first mechanistic study by which SAM68 modulates alternative splicing decision, by affecting U1 snRNP recruitment at 5' splice sites.Keywords
Funding Information
- Fonds de Recherche du Québec - Santé
- Natural Sciences and Engineering Research Council of Canada (402880-2012, 2016-05847)
This publication has 73 references indexed in Scilit:
- Stay lean without dietingAdipocyte, 2012
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- Widespread binding of FUS along nascent RNA regulates alternative splicing in the brainScientific Reports, 2012
- U1 snRNP Determines mRNA Length and Regulates Isoform ExpressionCell, 2012
- mTOR Signaling in Growth Control and DiseaseCell, 2012
- Coupled 5′ Nucleotide Recognition and Processivity in Xrn1-Mediated mRNA DecayMolecular Cell, 2011
- U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylationNature, 2010
- The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in spinal muscular atrophyThe EMBO Journal, 2010
- The Spliceosome: Design Principles of a Dynamic RNP MachineCell, 2009
- A point mutation in the FMR-1 gene associated with fragile X mental retardationNature Genetics, 1993