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Gemcitabine is the first-line treatment for locally advanced and metastatic gallbladder cancer (GBC), but poor gemcitabine response is universal. Here, we utilize a genome-wide CRISPR screen to identify that loss of ELP5 reduces the gemcitabine-induced apoptosis in GBC cells in a P53-dependent manner through the Elongator complex and other uridine 34 (U 34 ) tRNA-modifying enzymes. Mechanistically, loss of ELP5 impairs the integrity and stability of the Elongator complex to abrogate wobble U 34  tRNA modification, and directly impedes the wobble U 34  modification-dependent translation of hnRNPQ mRNA, a validated P53 internal ribosomal entry site (IRES)  trans -acting factor. Downregulated hnRNPQ is unable to drive P53 IRES-dependent translation, but rescuing a U 34  modification-independent hnRNPQ mutant could restore P53 translation and gemcitabine sensitivity in  ELP5 -depleted GBC cells. GBC patients with lower ELP5, hnRNPQ, or P53 expression have poor survival outcomes after gemcitabine chemotherapy. These results indicate that the Elongator/hnRNPQ/P53 axis controls gemcitabine sensitivity in GBC cells.

Genome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer