Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Semin Cell Dev Biol. 2014 Jun;30:110-20. doi: 10.1016/j.semcdb.2014.04.014. Epub 2014 Apr 13.
Replication origins are where pre-replication complexes are assembled during G1 phase. However, only a subset of the origins is actually "fired" to initiate DNA synthesis during S phase. Whereas factors involved in these steps are relatively well understood now, the mechanisms behind the origin specification, the choice of origins to be fired and determination of their timing are still under active investigation. Recent data show that the origin positions as well as the selection of those to be fired may be determined by multiple factors including sequences, chromatin context, epigenetic information, and some specific genomic features, but that the choice is surprisingly plastic and opportunistic. Timing regulation of firing, on the other hand, appears to be related to cell type-specific intrinsic chromatin architecture in nuclei. The conserved Rif1 protein appears to be a major global regulator of the genome-wide replication timing. Replication timing is regulated also by other factors including checkpoint signals, local chromatin structures, timing and quantity of pre-RC formation, and availability of limiting initiation factors.
复制起点是复制前复合物在 G1 期组装的地方。然而，只有一小部分起点实际上在 S 期被“触发”以启动 DNA 合成。虽然现在已经相对了解了涉及这些步骤的因素，但起源规范、被触发的起点的选择以及它们的时间确定的机制仍在积极研究中。最近的数据表明，起点的位置以及被触发的起点的选择可能由多个因素决定，包括序列、染色质环境、表观遗传信息和一些特定的基因组特征，但选择是惊人的灵活和机会主义的。另一方面，触发的时间调节似乎与核内特定细胞类型的固有染色质结构有关。保守的 Rif1 蛋白似乎是基因组范围复制时间的主要全局调节剂。复制时间也受到其他因素的调节，包括检查点信号、局部染色质结构、预 RC 形成的时间和数量以及限制起始因子的可用性。
