The origin recognition complex: from simple origins to complex functions

  1. Stephen P. Bell1
  1. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

This extract was created in the absence of an abstract.

Eukaryotic DNA replication is an intricate process that requires the coordinate and tightly regulated action of numerous molecular machines. Eukaryotic cells must choose hundreds if not thousands of origins of replication and assemble multiple proteins or protein complexes at these sites. During S phase, these complexes are activated in a reproducible, temporal program to generate twice this number of replication fork machines dedicated to DNA synthesis. Moreover, these machines must overcome the highly packaged nature of the eukaryotic genome to access all DNA sites, without exception.

The key factor in the selection of initiation sites and the assembly of the replication machinery is the initiator protein. Originally proposed by Brenner, Cuzin, and Jacob based on genetic findings, the replicon model hypothesized the existence of two essential components required for replication initiation: the initiator and the replicator (Jacob et al. 1963). The initiator is a positively acting factor that recognizes a specific DNA sequence within the genetic element required for initiation, called the replicator. The replicator usually overlaps the site of replication initiation, the origin of replication. Subsequent studies in Escherichia coli, other bacteria, and many bacteriophages and eukaryotic viruses identified initiator proteins and confirmed this basic model. Unlike these organisms, each of which uses a single replicator to duplicate their genome, eukaryotic chromosomes each require multiple replicators to ensure complete replication of their genome in a timely manner. Although it was possible that multiple initiators functioned in this more complex situation, studies over the last 10 years have demonstrated that a single conserved eukaryotic initiator directs all of these initiation events: the origin recognition complex (ORC).

The well-defined replicators of Saccharomyces cerevisiaeprovided the critical tools to identify ORC. These sequences were originally identified by their ability to confer stable propagation to yeast episomes and were called autonomous replicating …

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