Sivaprasad Umasundari, Machida Yuichi J, Dutta Anindya
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Cell Div. 2007 Feb 23;2:8. doi: 10.1186/1747-1028-2-8.
DNA replication must be tightly controlled to prevent initiation of a second round of replication until mitosis is complete. So far, components of the pre-replicative complex (Cdt1, Cdc6 and geminin) were considered key players in this regulation. In a new study, Machida and Dutta have shown that depletion of Emi1 caused cells to replicate their DNA more than once per cell cycle 1. This effect was dependent on the ability of Emi1 to inhibit the APC/C. In addition to its role in regulating entry into mitosis, oscillation of APC/C activity regulates pre-RC formation: high APC/C activity in late M/G1 allows pre-RC formation and low APC/C activity in S/G2 prevents pre-RC formation for a second time thereby preventing rereplication. Each redundant pathway to prevent rereplication is dependent on regulating one of the pre-RC components, and all of the pathways are co-regulated by Emi1 through the APC/C. In this commentary we discuss how this new role of Emi1 adds to our understanding of the regulation of replication initiation. We also review the literature to analyze whether APC/C has a role in regulating endoreduplication (a normal state of polyploidy in some differentiated cells). Similarly a role of premature APC/C activation in genomic instability of tumors is discussed.
DNA复制必须受到严格控制，以防止在有丝分裂完成之前启动第二轮复制。到目前为止，复制前复合体的组成部分（Cdt1、Cdc6和geminin）被认为是这种调控的关键因素。在一项新的研究中，町田和杜塔发现，Emi1的缺失导致细胞在每个细胞周期中不止一次复制其DNA 1。这种效应取决于Emi1抑制后期促进复合体/细胞周期体（APC/C）的能力。除了其在调控进入有丝分裂中的作用外，APC/C活性的振荡还调控复制前复合体的形成：M期/G1期后期的高APC/C活性允许复制前复合体形成，而S期/G2期的低APC/C活性则防止复制前复合体再次形成，从而防止重新复制。每条防止重新复制的冗余途径都依赖于对复制前复合体的一个组成部分的调控，并且所有这些途径都由Emi1通过APC/C共同调控。在这篇评论中，我们讨论了Emi1的这一新作用如何增进我们对复制起始调控的理解。我们还回顾了文献，以分析APC/C是否在调控核内复制（一些分化细胞中的一种正常多倍体状态）中发挥作用。同样，也讨论了APC/C过早激活在肿瘤基因组不稳定性中的作用。
