The translational regulator GCN20 regulates replication stress response

DNA replication stress seriously threatens genome stability and is a hall marker 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. However, the roles of translational control in DNA damage responses (DDR) is unknown. Here we show that ATR-WEE1 regulates the translation of SOG1, the master regulator of DNA damage responses in plants. Through genetic screening, we find that loss of GCN20 and GCN1, which functions together to inhibit protein translation, suppresses the hypersensitivity of Arabidopsis atr and wee1 to the replication stress-inducing agent hydroxyurea (HU). Biochemically, WEE1 directly interacts with and phosphorylates GCN20, which is further polyubiquitinated and degraded. Overexpression of GCN20 significantly inhibits the translation of SOG1. Genetically, mutation of SOG1 enhances the sensitivity of wee1 and wee1 gcn20 to HU, and overexpression of SOG1 suppresses the sensitivity of wee1 to HU. These results suggest that ATR-WEE1 inhibits GCN20-GCN1 to promote the translation of SOG1 during replication stress responses. Taken together, our study identifies a novel function of ATR-WEE1, reveals a new regulatory mechanism for SOG1, and links the translation control to DNA damage responses.