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Stress-induced splicing activation of immediate early genes by nuclear speckle reorganization [ANI]

ABSTRACT: Current models posit that nuclear speckles (NSs) serve as reservoirs of splicing factors and facilitate post-transcriptional processing of mRNA. Here, we discovered that ribotoxic stress leads to a profound reorganization of NSs with enhanced recruitment of factors required for 5' and 3' splice site recognition including the RNA-binding protein TIAR, U1 snRNP proteins and U2-associated factor 65, as well as serine 2 phosphorylated RNA polymerase II. NS reorganization is dependent on the stress-activated p38 mitogen activated protein kinase (MAPK), and goes along with splicing activation of both pre-existing and nascent pre-mRNAs. In particular, ribotoxic stress causes targeted excision of retained introns from pre-mRNAs of immediate early genes (IEGs), whose transcription is induced during the stress response. Importantly, enhanced splicing of the IEGs ZFP36 and FOS is accompanied by re-localization of the corresponding mRNAs to NSs. Our study reveals NSs as a dynamic compartment that is remodeled under stress conditions to promote the excision of retained introns and thereby enhance the expression and processing of IEG mRNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181446 | GEO | 2021/08/06

REPOSITORIES: GEO

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Stress-induced splicing activation of immediate early genes by nuclear speckle reorganization [ThioU]

Project description:Current models posit that nuclear speckles (NSs) serve as reservoirs of splicing factors and facilitate post-transcriptional processing of mRNA. Here, we discovered that ribotoxic stress leads to a profound reorganization of NSs with enhanced recruitment of factors required for 5' and 3' splice site recognition including the RNA-binding protein TIAR, U1 snRNP proteins and U2-associated factor 65, as well as serine 2 phosphorylated RNA polymerase II. NS reorganization is dependent on the stress-activated p38 mitogen activated protein kinase (MAPK), and goes along with splicing activation of both pre-existing and nascent pre-mRNAs. In particular, ribotoxic stress causes targeted excision of retained introns from pre-mRNAs of immediate early genes (IEGs), whose transcription is induced during the stress response. Importantly, enhanced splicing of the IEGs ZFP36 and FOS is accompanied by re-localization of the corresponding mRNAs to NSs. Our study reveals NSs as a dynamic compartment that is remodeled under stress conditions to promote the excision of retained introns and thereby enhance the expression and processing of IEG mRNAs.

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pre-mRNA splicing order is defined and maintains splicing fidelity across multi-intronic transcripts [I]

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