The authors found that DNA damage caused the nuclear accumulation of tRNAs containing unspliced introns, which are removed in the cytoplasm. This accumulation required the damage-induced signaling molecule Rad53 and correlated with the retention of the main tRNA export receptor, Los1, in the cytoplasm.
Without their exporter, tRNAs were stuck in the nucleus, causing cell cycle arrest in G1 and giving the cell time to repair damage before DNA synthesis. Deleting Rad53 prevented the nuclear tRNA build-up, and damaged cells exited G1 prematurely. Deleting Los1 in these cells restored the G1 arrest.
The G1 stall was not due to decreased cytoplasmic tRNA, which remained in large excess due to its long turnover time. Instead, the stall stemmed from the surplus of nuclear tRNA, which somehow enhanced translation of a stress response factor called Gcn4—a protein that promotes repair and slows the synthesis of G1 cyclins.
“This process couples the nuclear sensing of DNA damage to cytoplasmic protein synthesis,” Ghavidel says. “It was an entirely unanticipated mechanism, since tRNA export has traditionally been viewed as constitutive.”