An origin of replication is a sequence of DNA at which replication is started on a chromosome, plasmid or virus. For small DNAs, including bacterial plasmids and small viruses, a single origin is sufficient.
The development of molecular and biochemical approaches to identify start sites of DNA replication (origins) based on the presence of defining and characteristic replication intermediates at specific loci led to the identification of only a handful of mammalian replication origins. The limited number of identified origins prevented a comprehensive and exhaustive search for conserved genomic features that were capable of specifying origins of DNA replication.
The onset of genomic DNA synthesis requires precise interactions of specialized initiator proteins with DNA at sites where the replication machinery can be loaded. These sites, known as replication origins, are present at a few unique locations in all of the prokaryotic chromosomes examined so far. However, replication origins are dispersed among tens of thousands of loci in metazoan chromosomes. Close examination of bacterial and archaeal replication origins shows an array of DNA sequence motifs that position individual initiator protein molecules and promote initiator oligomerization on origin DNA. Conversely, the need for specific recognition sequences in eukaryotic replication origins is relaxed. In fact, the primary rule for origin selection appears to be flexibility, a feature that is modulated either by structural elements or by epigenetic mechanisms at least partly linked to the organization of the genome for gene expression. Ori-Finder and Boris tools are used to identify the origin replications in different organisms.
DNA replication origins can be present in the three forms:
- sites for binding of proteins, mainly initiation and auxiliary proteins
- a characteristically AT-rich region that is unwound
- sites and structural properties involved in regulating initiation events
Synthesis of daughter strands starts at replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Although the specific replication origin organization structure and recognition varies from species to species, some common characteristics are shared among origins for replications.
- DNA replication origins have a common 12 bp consensus sequence in S. cerevisiae. In Schizo saccharomyces pombe, DNA replication origins are characterized by AT-rich islands. In metazoans, both CpG islands and AT-rich stretches may characterize the origins.
- Replication origins are in excess relative to their use in each cell cycle. They fall into three main classes: used all the time (constitutive), used in an apparently stochastic manner in each cell cycle and used in specific growth or differentiation conditions (dormant).
- Replication stress and checkpoint controls can regulate the use of flexible origins and the activation of dormant origins and can repress late replication origins. Transcriptional features and development also modulate the use and position of the replication origins along the genome.
- Chromosome structure and chromatin organization have a big impact on origin selection and function.
- Replication origins are organized in clusters of consecutive origins that are synchronously activated.
- The origin of replication also determines the plasmid’s compatibility: its ability to replicate in conjunction with another plasmid within the same bacterial cell.