Caillat Christophe, Perrakis Anastassis
Department of Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Subcell Biochem. 2012;62:71-87. doi: 10.1007/978-94-007-4572-8_5.
One of the mechanisms controlling the initiation of DNA replication is the dynamic interaction between Cdt1, which promotes assembly of the pre-replication license complex, and Geminin, which inhibits it. Specifically, Cdt1 cooperates with the cell cycle protein Cdc6 to promote loading of the minichromosome maintenance helicases (MCM) onto the chromatin-bound origin recognition complex (ORC), by directly interacting with the MCM complex, and by modulating histone acetylation and inducing chromatin unfolding. Geminin, on the other hand, prevents the loading of the MCM onto the ORC both by directly binding to Cdt1, and by modulating Cdt1 stability and activity. Protein levels of Geminin and Cdt1 are tightly regulated through the cell cycle, and the Cdt1-Geminin complex likely acts as a molecular switch that can enable or disable the firing of each origin of replication. In this review we summarize structural studies of Cdt1 and Geminin and subsequent insights into how this molecular switch may function to ensure DNA is faithfully replicated only once during S phase of each cell cycle.
控制DNA复制起始的机制之一是促进复制前许可复合物组装的Cdt1与抑制该复合物的Geminin之间的动态相互作用。具体而言，Cdt1与细胞周期蛋白Cdc6协同作用，通过直接与MCM复合物相互作用、调节组蛋白乙酰化并诱导染色质解折叠，促进微型染色体维持解旋酶（MCM）加载到与染色质结合的起始识别复合物（ORC）上。另一方面，Geminin通过直接结合Cdt1以及调节Cdt1的稳定性和活性，阻止MCM加载到ORC上。Geminin和Cdt1的蛋白质水平在整个细胞周期中受到严格调控，并且Cdt1-Geminin复合物可能充当分子开关，能够启用或禁用每个复制起点的启动。在本综述中，我们总结了Cdt1和Geminin的结构研究以及随后对该分子开关如何发挥作用以确保DNA在每个细胞周期的S期仅忠实地复制一次的见解。
