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The Gpn3 Q279* cancer‐associated mutant inhibits Gpn1 nuclear export and is deficient in RNA polymerase II nuclear targeting

Gpn3 is required for RNA polymerase II (RNAPII) nuclear targeting. Here, we investigated the effect of a cancer‐associated Q279* nonsense mutation in Gpn3 cellular function. Employing RNAi, we replaced endogenous Gpn3 by wt or Q279* RNAi‐resistant Gpn3R in epithelial model cells. RNAPII nuclear accumulation and transcriptional activity were markedly decreased in cells expressing only Gpn3R Q279*. Wild‐type Gpn3R localized to the cytoplasm but a fraction of Gpn3R Q279* entered the cell nucleus and inhibited Gpn1‐EYFP nuclear export. This property and the transcriptional deficit in Gpn3R Q279*‐expressing cells required a PDZ‐binding motif generated by the Q279* mutation. We conclude that an acquired PDZ‐binding motif in Gpn3 Q279* caused Gpn3 nuclear entry, and inhibited Gpn1 nuclear export and Gpn3‐mediated RNAPII nuclear targeting.