title: Mechanisms and regulation of DNA replication initiation in eukaryotes.
abstract: Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a typical cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re-replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the origin recognition complex (ORC), and subsequent activation of the helicase by its incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here, we review the molecular mechanisms that underpin eukaryotic DNA replication initiation - from selecting replication start sites to replicative helicase loading and activation - and describe how these events are often distinctly regulated across different eukaryotic model organisms.
authors.affiliation: a Department of Biophysics and Biophysical Chemistry , Johns Hopkins University School of Medicine , Baltimore , MD , USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Parker
authors.affiliation: b Department of Molecular and Cell Biology , University of California Berkeley , Berkeley , CA , USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Botchan
authors.affiliation: a Department of Biophysics and Biophysical Chemistry , Johns Hopkins University School of Medicine , Baltimore , MD , USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Berger
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004789:Enzyme Activation; D005057:Eukaryotic Cells / Q000378:metabolism*; D006801:Humans; D064110:Minichromosome Maintenance Proteins / Q000032:analysis / Q000378:metabolism; D051738:Origin Recognition Complex / Q000032:analysis / Q000378:metabolism; D018741:Replication Origin
chemical_list: D002843:Chromatin; D051738:Origin Recognition Complex; D064110:Minichromosome Maintenance Proteins
keywords: CMG; Cdc6; Cdt1; DNA replication; MCM2-7; ORC; helicase; initiator