The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells [CLIP-seq and mRNA-seq]

However, the mechanisms behind sustained protein synthesis during ISR activation remain unclear. In eukaryotic cells, the 5′-cap of most mRNAs is bound either by the nuclear cap-binding complex (CBC) or by the cytosolic cap-binding protein eIF4E.

Our study reveals that under stress conditions, CBC-bound mRNAs utilize eIF2A, an alternative translation initiation factor, to maintain protein synthesis when translation of eIF4E-bound mRNAs is significantly inhibited. Human embryonic stem cells (hESCs), which inherently exhibit ISR, continue active proliferation due to a compensatory increase in eIF2A expression. This increase ensures CBC-dependent translation (CT) and supports the synthesis of essential cell cycle proteins during stress.