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mTOR-driven widespread exon skipping renders multifaceted gene regulation and proteome complexity

By Sze Cheng, Naima Ahmed Fahmi, Meeyeon Park, Jae-Woong Chang, Jiao Sun, Kaitlyn Thao, Hsin-Sung Yeh, Wei Zhang, Jeongsik Yong

Posted 27 Feb 2020
bioRxiv DOI: 10.1101/2020.02.27.967737

The mammalian target of rapamycin (mTOR) pathway is crucial in cell proliferation. Previously, we reported transcriptome-wide 3-untranslated region (UTR) shortening by alternative polyadenylation upon mTOR activation and its impact on the proteome. Here, we further interrogated the mTOR-activated transcriptome and found that hyperactivation of mTOR promotes transcriptome-wide exon-skipping/exclusion, producing short isoform transcripts from genes. This widespread exon skipping confers multifarious regulations in the mTOR-controlled functional proteomics: alternative splicing (AS) in the 5-UTR controls translation efficiency while AS in coding regions widely affects the protein length and functional domains. They also alter the half-life of proteins and affect the regulatory post-translational modifications. Among the RNA processing factors differentially regulated by mTOR signaling, we found that SRSF3 mechanistically facilitates exon skipping in the mTOR-activated transcriptome. This study reveals a role of mTOR in AS regulation and demonstrates that widespread AS is a multifaceted modulator of the mTOR-regulated functional proteome. ### Competing Interest Statement The authors have declared no competing interest.

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