37 DNA Replication in Mammals

Abstract

Formulated in the early 1960s, the replicon hypothesis proposed that DNA synthesis is controlled by the interaction of initiator proteins with genetic elements termed replicators (Jacob et al. 1964). Study of the interaction of purified initiator proteins with cis-acting replicators from bacterial chromosomes, bacteriophage, and eukaryotic viruses has led to a general model for the assembly of replication forks at physically defined sites, or origins of replication (Bramhill and Kornberg 1988). In prokaryotes and viruses, the genome commonly consists of a single replicon, with a single replicator controlling initiation of DNA synthesis under all growth conditions. In higher eukaryotes, the genome consists of hundreds to thousands of replicons, and the order of replicon synthesis may vary as a function of growth conditions or cellular differentiation. Since the decision to initiate DNA synthesis is a critical point of control in the cell cycle, there is considerable interest in the structure of eukaryotic replicators and the factors that regulate their selection and activity under various conditions. Although the replicators of mammalian chromosomes and their cognate initiators have yet to be described, the basic unit of DNA synthesis remains the replicon.

REPLICONS AND REPLICON CLUSTERS IN MAMMALIAN CELLS
DNA fiber autoradiography has shown that mammalian DNA replication is usually bidirectional, with equivalent rates of synthesis at each of the two forks in a replication bubble; that initiation begins at multiple, dispersed sites spaced 50–250 kb apart; and that initiation within clusters of contiguous replicons tends to be coordinately controlled (Huberman and Riggs...