Human Inositol Polyphosphate Multikinase Regulates Transcript-Selective Nuclear mRNA Export to Preserve Genome Integrity

• Human IPMK selectively regulates the nuclear export of a subset of human mRNAs
• IPMK depletion affects mRNAs for genome integrity proteins, causing instability
• Recognition of a motif in the UTR of a target mRNA by ALY requires IPMK
• The IPMK product PIP3 restores target UTR recognition by ALY when IPMK is absent

SummaryMessenger RNA (mRNA) export from the nucleus is essential for eukaryotic gene expression. Here we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export. IPMK depletion or catalytic inactivation selectively decreases RAD51 protein abundance and the nuclear export of RAD51 mRNA, thereby impairing HR. Recognition of a sequence motif in the untranslated region of RAD51 transcripts by the mRNA export factor ALY requires IPMK. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), an IPMK product, restores ALY recognition in IPMK-depleted cell extracts, suggesting a mechanism underlying transcript selection. Our findings implicate IPMK in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans.

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