Cancer associated eIF1A mutants impair Rps3/Rps10 binding and enhance scanning of cell cycle genes

Protein synthesis is linked to cell proliferation, and its deregulation contributes
to cancer. Eukaryotic translation initiation factor 1A (eIF1A) plays a key role
in scanning and AUG selection and differentially affects the translation of distinct
mRNAs. Its unstructured N-terminal tail (NTT) is frequently mutated in several malignancies.
Here we report that eIF1A is essential for cell proliferation and cell cycle
progression. Ribosome profiling of eIF1A knockdown cells revealed a substantial enrichment
of cell cycle mRNAs among the downregulated genes, which are predominantly
characterized by a lengthy 5= untranslated region (UTR). Conversely, eIF1A depletion
caused a broad stimulation of 5= UTR initiation at a near cognate AUG,
unveiling a prominent role of eIF1A in suppressing 5= UTR translation. In addition,
the AUG context-dependent autoregulation of eIF1 was disrupted by eIF1A depletion,
suggesting their cooperation in AUG context discrimination and scanning. Importantly,
cancer-associated eIF1A NTT mutants augmented the eIF1A positive effect
on long 5= UTRs, while they hardly affected AUG selection. Mechanistically, these
mutations diminished the eIF1A interaction with Rps3 and Rps10 implicated in scanning
arrest. Our findings suggest that the reduced binding of eIF1A NTT mutants
to the ribosome retains its open state and facilitates scanning of long 5= UTRcontaining
cell cycle genes.