From G1 regulators to Replication machinery

G1信号激活Cdk4-CyclinD，进而通过Rb磷酸化激活E2F。我们的研究结果表明，E2F不仅诱导G1-S过渡所需的因子，还诱导S期调节因子、检查点蛋白、修复因子和G2-M过渡因子。这将导致生长周期的激活，并带来S期的协调进展以及随后的有丝分裂事件。由E2F诱导的复制因子促进染色质上复制前复合物的产生。这一过程可能与复制机制通过转录因子与核基质的相互作用密切相关。Cdk和Cdc7磷酸化MCM2和MCM4蛋白的n端尾部，这种磷酸化导致包括Cdc45在内的额外复制因子的募集。MCM解旋酶被在这一步骤中暴露的单链富硫胺序列特异性激活。在复制叉的操作过程中，多个夹子-夹子装载系统运行，允许协调执行叉相关活动，包括DNA合成，姐妹染色单体内聚和染色质组装。tti -potent干细胞经历特定的细胞周期程序，这可能是通过过度表达关键的复制/细胞周期调节子子集来实现的。在癌细胞中，复制因子的稳态表达水平与正常细胞明显不同，癌细胞中复制因子的下调通常会导致细胞死亡，这使得复制因子可能成为癌症治疗的新靶点。另一方面，包括Cdt1在内的一些关键因子的失调会导致诱导的遗传不稳定，从而可能导致恶性生长。

G1 signals activate Cdk4-CyclinD, which in turn activates E2F by phosphorylation of Rb. Our results show that E2F induces not only factors required for G1-S transition but also S phase regulators, checkpoint proteins, repair factors and G2-M transition factors. This will lead to activation of growth cycle and brings about coordinated progression of S phase as well as subsequent mitotic events. Replication factors induced by E2F promote generation of prereplicative complexes on the chromatin. This process may be intimately linked to interaction of replication machinery with nuclear matrix through transcription factors. Cdk and Cdc7 phosphorylates the N-terminal tails of MCM2 and MCM4 proteins and this phosphorylation results in recruitment of additional replication factors including Cdc45. MCM helicase is activated specifically by the single-stranded thimine-rich sequences which may be exposed during this step. Multiple clamp-clamp loader systems operate during the operation of replication forks, permitting the coordinated execution of fork-related activities including DNA synthesis, sister chromatid cohesion, and chromatin assembly. Tauti-potent stem cells undergo specific cell cycle program which may be achieved by overexpression of a subset of crucial replication/ cell cycle regulators. In cancer cells, the steady-state expression levels of the replication factors are distinctively different from the normal cells, and downregulation of replication factors in cancer cells often leads to induction of cell death, raising a possibility that replication factors could be novel targets for cancer therapy. On the other hand, deregulation of some critical factors including Cdt1 leads to induced genetic instability which may results in malignant growth.