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A Novel Role for Nucleolin in Splice Site Selection

ABSTRACT: A Novel Role for Nucleolin in Splice Site Selection

PROVIDER: PRJNA598591 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10815047_1.fastq.gz	Fastqsanger.gz
	SRR10815047_2.fastq.gz	Fastqsanger.gz
	SRR10815048_1.fastq.gz	Fastqsanger.gz
	SRR10815048_2.fastq.gz	Fastqsanger.gz
	SRR10815049_1.fastq.gz	Fastqsanger.gz

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A Novel Role for Nucleolin in Splice Site Selection

Project description:In search for nuclear partners of initiator-tRNA, previously shown to be involved in a quality control of splice site selection, we identified nucleolin (NCL) as specifically and directly bound to it in the nucleus and not in the cytoplasm (using affinity purification of UV crosslinked nuclear initiator-tRNA followed by mass spectrometry). To further explore the role of NCL in splice site selection, we knocked down NCL. We report the activation of 399 latent splice sites upon NCL knockdown, as revealed by RNA deep sequencing of siRNA treated NCL compared to control siRNA. Our study identifies NCL as the first protein component of this quality control mechanism of splice site selection. Our study thus establishes an experimental strategy and computational pipeline that could be used to identify other components of this quality control mechanism.

2022-03-08 | GSE142836 | GEO

A novel role for nucleolin in splice site selection.

Project description:Latent 5' splice sites, not normally used, are highly abundant in human introns, but are activated under stress and in cancer, generating thousands of nonsense mRNAs. A previously proposed mechanism to suppress latent splicing was shown to be independent of NMD, with a pivotal role for initiator-tRNA independent of protein translation. To further elucidate this mechanism, we searched for nuclear proteins directly bound to initiator-tRNA. Starting with UV-crosslinking, we identified nucleolin (NCL) interacting directly and specifically with initiator-tRNA in the nucleus, but not in the cytoplasm. Next, we show the association of ini-tRNA and NCL with pre-mRNA. We further show that recovery of suppression of latent splicing by initiator-tRNA complementation is NCL dependent. Finally, upon nucleolin knockdown we show activation of latent splicing in hundreds of coding transcripts having important cellular functions. We thus propose nucleolin, a component of the endogenous spliceosome, through its direct binding to initiator-tRNA and its effect on latent splicing, as the first protein of a nuclear quality control mechanism regulating splice site selection to protect cells from latent splicing that can generate defective mRNAs.

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Real-time visualization of spliceosome assembly reveals basic principles of splice site selection

Project description:The spliceosome is a megadalton protein-RNA complex which removes introns from pre-mRNA, yet the dynamic early assembly steps have not been structurally resolved. Specifically, how the spliceosome selects the correct 3’ splice site (3’SS) amongst highly similar non-functional sites is not known. Here, we develop a kinetic model of splice site selection based on single-molecule U2AF heterodimer imaging in vitro and in vivo. The model successfully predicts alternative splicing patterns and indicates that 3’SS selection occurs while U2AF is in complex with the spliceosome, not during initial binding. This finding indicates the spliceosome operates in a ‘partial’ kinetic proofreading regime, catalyzed in part by the helicase DDX42, which increases selectivity to the underlying U2AF binding site while still allowing for efficient forward progression.

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Project description:Real-time visualization of spliceosome assembly reveals basic principles of splice site selection

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Cancer associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point

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