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DNA replication, a vital process in all biological systems, ensures the faithful transfer of genetic information from parent to progeny organisms, and constitutes the major determinant of cell proliferation. This process can be arbitrarily divided into three steps: Initiation, which activates the template DNA to facilitate the incorporation of the first nucleotide in the daughter strands; elongation, which allows further incorporation of nucleotides; and termination, which culminates with the production of two equal copies of the parental DNA. Of these three steps, initiation is the ultimate and critical step in the regulation of cell proliferation.
The replicon model proposed nearly 50 years ago by Jacob, Brenner, and Cuzin [1], has served as a good paradigm for understanding the initiation step of DNA replication. According to this model, initiation of DNA replication depends on the interaction of trans-acting factors (initiators) with cis- acting DNA sequences (replicators or origins).The origin, and adjacent DNA sequences whose replication depend on it, define an independent unit of replication, or replicon. Based on studies on the single replicon present in E.coli, the role of the initiator protein(s) has been expanded to not only to mark the position of the origin, but as a recruitment factor that facilitates the opening of the DNA helix, a step required for the initiation of DNA synthesis [2]. In contrast to bacterial genomes, eukaryotic genomes are composed of thousands of replicons, thus, their replication occurs in a segmental fashion [3-5]. Eukaryotic replication typically follows three cardinal rules: (a) replication is restricted to the S-phase of the cell cycle; (b) replicons are activated in a specific temporal order, some initiating early, and others late in the S phase [6], and (c) for any given replicon, replication occurs only once per S phase and thus re-initiation is prevented [7-8].
Initiation of Eukaryotic DNA Replication
The dissection of the initiation step of DNA replication in eukaryotes requires the answer to three specific questions; How are DNA sites containing origins activated only once during each cell cycle?; What determines When origins fire during the S phase?; and Where are origins localized along each of the chromosomes? At present our knowledge of the how, when, and where of initiation of DNA replication is not complete. A great deal is known about how origins are activated, but less information has been gathered about the underlying mechanisms behind the temporal order of origin firing, as well as, about their chromosomal distribution. Therefore, a coherent picture regarding the relationship between these properties, and how this provides the framework for its regulation, remains to be elucidated. In this paper I wish to present an overview of the current literature in the field with a focus on research in mammalian systems, and in particular, human cells. More comprehensive reviews dealing with several aspects of the initiation process in eukaryotes, methodological approaches used, and the potential misregulation of this process leading to cancer, are available. These include an excellent collection grouped in a special January 2010 issue of Chromosome Research [9], as well as others published elsewhere [10-14].
Citation: Valenzuela MS (2012) Initiation of DNA Replication in the Human Genome. Hereditary Genetics S1:003 doi: 10.4172/2161-1041.S1-003
