Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA.
Mol Cell. 2018 Jan 4;69(1):24-35.e5. doi: 10.1016/j.molcel.2017.11.035. Epub 2017 Dec 28.
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.
保护和有效重启停滞的复制叉对于维持基因组完整性至关重要。在这里，我们确定了一个调控途径，可促进复制压力下停滞的叉恢复。我们表明，哺乳动物复制体成分 C20orf43/RTF2（与 S. pombe Rtf2 同源）必须被移除，才能使叉最佳重启。我们进一步表明，蛋白酶体穿梭蛋白 DDI1 和 DDI2 对于 RTF2 从停滞的叉上的移除是必需的。RTF2 在停滞的叉上的持续存在导致叉重启缺陷、DNA 损伤信号的过度激活、单链 DNA（ssDNA）的积累、对复制药物的敏感性以及染色体不稳定性。这些结果表明，RTF2 的去除是细胞应对复制压力和维持基因组完整性的关键决定因素。
