The ATR-WEE1 module inhibits GCN20-GCN1 to promote the translation of SOG1 to activate replication stress responses

DNA replication stress seriously threatens genome stability and is a hallmark of cancers. The evolutionarily conserved kinase ATR and WEE1 are essential for the activation of replication stress responses, but the underlying mechanisms are not well-understood. Translational control is an important mechanism to regulate gene expression, but its roles in replication stress responses is largely unknown. Here we show that ATR-WEE1 controls the translation of SOG1, a master transcription factor required for replication stress responses in Arabidopsis. Through genetic screening, we find that loss of GCN20 or GCN1, which functions together to inhibit protein translation, suppresses the hypersensitivity of the atr or wee1 mutants to the replication stress. Biochemically, WEE1 inhibits GCN20 by phosphorylating GCN20, which is further polyubiquitinated and degraded. Ribosome profiling experiments reveal that loss of GCN20 enhances the translation efficiency of SOG1, while overexpression of GCN20 reduces it. In consistence, loss of SOG1 reduces the resistance of wee1 gcn20 to HU, and overexpression of SOG1 enhances the resistance to atr or wee1 to HU. These results suggest that ATR-WEE1 inhibits GCN20-GCN1 to promote the translation of SOG1 during replication stress. Taken together, our study uncovers a novel function of ATR-WEE1 and a new regulatory mechanism for SOG1, linking translational control to replication stress responses.