Cancer Research UK London Research Institute (LRI), Clare Hall Laboratories, South Mimms, Herts., UK.
Science. 2013 May 24;340(6135):981-4. doi: 10.1126/science.1237448.
Treslin/TICRR (TopBP1-interacting, replication stimulating protein/TopBP1-interacting, checkpoint, and replication regulator), the human ortholog of the yeast Sld3 protein, is an essential DNA replication factor that is regulated by cyclin-dependent kinases and the DNA damage checkpoint. We identified MDM two binding protein (MTBP) as a factor that interacts with Treslin/TICRR throughout the cell cycle. We show that MTBP depletion by means of small interfering RNA inhibits DNA replication by preventing assembly of the CMG (Cdc45-MCM-GINS) holohelicase during origin firing. Although MTBP has been implicated in the function of the p53 tumor suppressor, we found MTBP is required for DNA replication irrespective of a cell's p53 status. We propose that MTBP acts with Treslin/TICRR to integrate signals from cell cycle and DNA damage response pathways to control the initiation of DNA replication in human cells.
Treslin/TICRR（TopBP1 相互作用、复制刺激蛋白/TopBP1 相互作用、检查点和复制调节剂）是酵母 Sld3 蛋白的人类同源物，是一种必需的 DNA 复制因子，受细胞周期蛋白依赖性激酶和 DNA 损伤检查点调控。我们发现 MDM2 结合蛋白（MTBP）是一种在整个细胞周期与 Treslin/TICRR 相互作用的因子。我们表明，通过小干扰 RNA 耗尽 MTBP 会通过阻止起始原点处 CMG（Cdc45-MCM-GINS）全旋酶的组装来抑制 DNA 复制。尽管 MTBP 已被牵涉到 p53 肿瘤抑制因子的功能中，但我们发现 MTBP 对于 DNA 复制是必需的，而与细胞的 p53 状态无关。我们提出，MTBP 与 Treslin/TICRR 一起作用，整合来自细胞周期和 DNA 损伤反应途径的信号，以控制人类细胞中 DNA 复制的起始。
