DNA Replication-Initiation Proteins in Eukaryotic Cells

DNA replication is a highly regulated cellular process in proliferating cells, involving cell cycle dependent assembly of DNA replication-initiation proteins (DRIPs) onto origins of replication. The process of pre-replicative complex (pre-RC) formation at the M-to-G1 transition, also known as replication licensing, requires origin recognition complex (Orc1-6p) that binds and marks replication origins to facilitate the loading of additional DRIPs, such as Noc3p, Ipi3p, Cdc6p, Cdt1p and Mcm2-7p. The subsequent activation of pre-RC at the 1-to-S transition is dependent upon cyclin-dependent kinases (CDKs) and Dbf4-dependent kinase (DDK). This sequential process ensures that DRIPs are precisely loaded to form pre-ICs and then activated by their regulators so that chromosomal DNA is replicated only once per cell cycle. Despite substantial gains in the study of the mechanisms and regulation of pre-RC, the finite details of the pre-RC assembly and disassembly processes remain unclear and controversial. In this review we describe the present state of understanding on DRIPs and the pre-RC architecture and dynamics.