A twin UGUA motif directs the balance between gene isoforms through CFIm and the mTORC1 signaling pathway.

Autor:	Herron RS; Department of Pathology, University of Pittsburgh, Pittsburgh, United States., Kunisky AK; Department of Pathology, University of Pittsburgh, Pittsburgh, United States., Madden JR; Department of Pathology, University of Pittsburgh, Pittsburgh, United States., Anyaeche VI; Department of Pathology, University of Pittsburgh, Pittsburgh, United States., Maung MZ; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States., Hwang HW; Department of Pathology, University of Pittsburgh, Pittsburgh, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Sep 04; Vol. 12. Date of Electronic Publication: 2023 Sep 04.
DOI:	10.7554/eLife.85036
Abstrakt:	Alternative polyadenylation (APA) generates mRNA isoforms and diversifies gene expression. Here we report the discovery that the mTORC1 signaling pathway balances the expression of two Trim9/TRIM9 isoforms through APA regulation in human and mouse. We showed that CFIm components, CPSF6 and NUDT21, promote the short Trim9/TRIM9 isoform ( Trim9-S/TRIM9-S ) expression. In addition, we identified an evolutionarily conserved twin UGUA motif, UGUAYUGUA, in TRIM9-S polyadenylation site (PAS) that is critical for its regulation by CPSF6. We found additional CPSF6-regulated PASs with similar twin UGUA motifs in human and experimentally validated the twin UGUA motif functionality in BMPR1B , MOB4 , and BRD4-L . Importantly, we showed that inserting a twin UGUA motif into a heterologous PAS was sufficient to confer regulation by CPSF6 and mTORC1. Our study reveals an evolutionarily conserved mechanism to regulate gene isoform expression by mTORC1 and implicates possible gene isoform imbalance in cancer and neurological disorders with mTORC1 pathway dysregulation. Competing Interests: RH, AK, JM, VA, MM, HH No competing interests declared (© 2023, Herron et al.)
Databáze:	MEDLINE
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