The protection and efficient restart of stalled replication forks is critical for the maintenance of genome integrity. Here, we identify a regulatory pathway that promotes stalled forks recovery from replication stress. We show that the mammalian replisome component C20orf43/RTF2 (homologous to S. pombe Rtf2) must be removed for fork restart to be optimal. We further show that the proteasomal shuttle proteins DDI1 and DDI2 are required for RTF2 removal from stalled forks. Persistence of RTF2 at stalled forks results in fork restart defects, hyperactivation of the DNA damage signal, accumulation of single-stranded DNA (ssDNA), sensitivity to replication drugs, and chromosome instability. These results establish that RTF2 removal is a key determinant for the ability of cells to manage replication stress and maintain genome integrity.

停滞的复制叉的保护和有效重启对于维持基因组完整性至关重要。在这里，我们确定了一条促进停滞的叉子从复制压力中恢复的调控途径。我们显示，哺乳动物复制体成分C20orf43 / RTF2（与粟酒裂殖酵母同源必须将Rtf2）删除，以使分叉重新启动达到最佳状态。我们进一步表明蛋白酶体穿梭蛋白DDI1和DDI2是从停滞的叉中去除RTF2所必需的。RTF2在停滞的货叉上的持久性会导致货叉重启缺陷，DNA损伤信号的过度活化，单链DNA（ssDNA）的积累，对复制药物的敏感性以及染色体不稳定。这些结果证明，RTF2的去除是决定细胞处理复制压力和维持基因组完整性的关键因素。