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

The integrated stress response (ISR) suppresses global translation while allowing the selective translation of key regulatory genes. 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. Furthermore, we identify YAP, a master regulator of cell proliferation, as a critical target of CT, driving stress-resistant proliferation in stem cells. Collectively, our findings highlight CT as a crucial pathway that protects protein synthesis and supports stem cell proliferation during stress.