Origin of replication - Misplaced Pages

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The origin of replication (also called the replication origin) is a particular sequence in a genome at which replication is initiated. This can either involve the replication of DNA in living organisms such as prokaryotes and eukaryotes, or that of DNA or RNA in viruses, such as double-stranded RNA viruses.

DNA replication may proceed from this point bidirectionally or unidirectionally.

The specific structure of the origin of replication varies somewhat from species to species, but all share some common characteristics such as high AT content (repeats of adenine and thymine are easier to separate because their base stacking interactions are not as strong as those of guanine and cytosine). The origin of replication binds the pre-replication complex, a protein complex that recognizes, unwinds, and begins to copy DNA.

Types

There are also significant differences between prokaryotic and eukaryotic origins of replication:

Most bacteria have a single circular molecule of DNA, and typically only a single origin of replication per circular chromosome.
Most archaea have a single circular molecule of DNA, and several origins of replication along this circular chromosome.
Eukaryotes often have multiple origins of replication on each linear chromosome that initiate at different times (replication timing), with up to 100,000 present in a single human cell. Having many origins of replication helps to speed the duplication of their (usually) much larger store of genetic material. The segment of DNA that is copied starting from each unique replication origin is called a replicon. The replicons range from 40 kb length, in yeast and Drosophila, to 300 kb in plants.
Mitochondrial DNA in many organisms has two ori sequences. In humans, they are called oriH and oriL for the heavy and light strand of the DNA, each being the origin of replication for single-stranded replication. The two Chloroplast DNA ori sequences in Nicotiana tabacum, the tobacco plant, has been characterized as oriA and oriB.

Origins of replication are typically assigned names containing "ori". When it comes to plasmids, origins of replication are classified in two ways:

Narrow or broad host range
High- or low-copy number.

Bacterial

Most bacterial chromosomes are circular and contain a single origin of chromosomal replication (oriC). Bacterial oriC regions are surprisingly diverse in size (ranging from 250 bp to 2 kbp), sequence, and organization; nonetheless, their ability to drive replication onset typically depends on sequence-specific readout of consensus DNA elements by the bacterial initiator, a protein called DnaA. Origins in bacteria are either continuous or bipartite and contain three functional elements that control origin activity: conserved DNA repeats that are specifically recognized by DnaA (called DnaA-boxes), an AT-rich DNA unwinding element (DUE), and binding sites for proteins that help regulate replication initiation (for reviews, see ; Figure 2A). Interactions of DnaA both with the double-stranded (ds) DnaA-box regions and with single-stranded (ss) DNA in the DUE are important for origin activation and are mediated by different domains in the initiator protein: a Helix-turn-helix (HTH) DNA binding element and an ATPase associated with various cellular activities (AAA+) domain, respectively (Figure 2B). While the sequence, number, and arrangement of origin-associated DnaA-boxes vary throughout the bacterial kingdom, their specific positioning and spacing in a given species are critical for oriC function and for productive initiation complex formation.

Among bacteria, E. coli is a particularly powerful model system to study the organization, recognition, and activation mechanism of replication origins. E. coli oriC comprises an approximately ~260 bp region containing four types of initiator binding elements that differ in their affinities for DnaA and their dependencies on the co-factor ATP (Figure 2A). DnaA-boxes R1, R2, and R4 constitute high-affinity sites that are bound by the HTH domain of DnaA irrespective of the nucleotide-binding state of the initiator. By contrast, the I, τ, and C-sites, which are interspersed between the R-sites, are low-affinity DnaA-boxes and associate preferentially with ATP-bound DnaA, although ADP-DnaA can substitute for ATP-DnaA under certain conditions. Binding of the HTH domains to the high- and low-affinity DnaA recognition elements promotes ATP-dependent higher-order oligomerization of DnaA’s AAA+ modules into a right-handed filament that wraps duplex DNA around its outer surface, thereby generating superhelical torsion that facilitates melting of the adjacent AT-rich DUE (Figure 2C). DNA strand separation is additionally aided by direct interactions of DnaA’s AAA+ ATPase domain with triplet repeats, so-called DnaA-trios, in the proximal DUE region. The engagement of single-stranded trinucleotide segments by the initiator filament stretches DNA and stabilizes the initiation bubble by preventing reannealing. The DnaA-trio origin element is conserved in many bacterial species, indicating it is a key element for origin function. After melting, the DUE provides an entry site for the E. coli replicative helicase DnaB, which is deposited onto each of the single DNA strands by its loader protein DnaC .

Although the different DNA binding activities of DnaA have been extensively studied biochemically and various apo, ssDNA-, or dsDNA-bound structures have been determined, the exact architecture of the higher-order DnaA-oriC initiation assembly remains unclear. Two models have been proposed to explain the organization of essential origin elements and DnaA-mediated oriC melting. The two-state model assumes a continuous DnaA filament that switches from a dsDNA binding mode (the organizing complex) to an ssDNA binding mode in the DUE (the melting complex) (Figure 2C, left panel). By contrast, in the loop-back model, the DNA is sharply bent in oriC and folds back onto the initiator filament so that DnaA protomers simultaneously engage double- and single-stranded DNA regions (Figure 2C, right panel). Elucidating how exactly oriC DNA is organized by DnaA remains thus an important task for future studies. Insights into initiation complex architecture will help explain not only how origin DNA is melted, but also how a replicative helicase is loaded directionally onto each of the exposed single DNA strands in the unwound DUE, and how these events are aided by interactions of the helicase with the initiator and specific loader proteins.

Archaeal

Archaeal replication origins share some but not all of the organizational features of bacterial oriC. Unlike bacteria, Archaea often initiate replication from multiple origins per chromosome (one to four have been reported); yet, archaeal origins also bear specialized sequence regions that control origin function (for recent reviews, see ). These elements include both DNA sequence-specific origin recognition boxes (ORBs or miniORBs) and an AT-rich DUE that is flanked by one or several ORB regions. ORB elements display a considerable degree of diversity in terms of their number, arrangement, and sequence, both among different archaeal species and among different origins within in a single species. An additional degree of complexity is introduced by the initiator, Orc1/Cdc6 in archaea, which binds to ORB regions. Archaeal genomes typically encode multiple paralogs of Orc1/Cdc6 that vary substantially in their affinities for distinct ORB elements and that differentially contribute to origin activities. In Sulfolobus solfataricus, for example, three chromosomal origins have been mapped (oriC1, oriC2, and oriC3; Figure 3A), and biochemical studies have revealed complex binding patterns of initiators at these sites (Figure 3B). The cognate initiator for oriC1 is Orc1-1, which associates with several ORBs at this origin. OriC2 and oriC3 are bound by both Orc1-1 and Orc1-3. Conversely, a third paralog, Orc1-2, footprints at all three origins but has been postulated to negatively regulate replication initiation. Additionally, the WhiP protein, an initiator unrelated to Orc1/Cdc6, has been shown to bind all origins as well and to drive origin activity of oriC3 in the closely related Sulfolobus islandicus. Because archaeal origins often contain several adjacent ORB elements, multiple Orc1/Cdc6 paralogs can be simultaneously recruited to an origin and oligomerize in some instances; however, in contrast to bacterial DnaA, formation of a higher-order initiator assembly does not appear to be a general prerequisite for origin function in the archaeal domain.

Structural studies have provided insights into how archaeal Orc1/Cdc6 recognizes ORB elements and remodels origin DNA. Orc1/Cdc6 paralogs are two-domain proteins and are composed of a AAA+ ATPase module fused to a C-terminal winged-helix fold (Figure 3C). DNA-complexed structures of Orc1/Cdc6 revealed that ORBs are bound by an Orc1/Cdc6 monomer despite the presence of inverted repeat sequences within ORB elements. Both the ATPase and winged-helix regions interact with the DNA duplex but contact the palindromic ORB repeat sequence asymmetrically, which orients Orc1/Cdc6 in a specific direction on the repeat. Interestingly, the DUE-flanking ORB or miniORB elements often have opposite polarities, which predicts that the AAA+ lid subdomains and the winged-helix domains of Orc1/Cdc6 are positioned on either side of the DUE in a manner where they face each other (Figure 3B, bottom panel). Since both regions of Orc1/Cdc6 associate with a minichromosome maintenance (MCM) replicative helicase, this specific arrangement of ORB elements and Orc1/Cdc6 is likely important for loading two MCM complexes symmetrically onto the DUE (Figure 3B). Surprisingly, while the ORB DNA sequence determines the directionality of Orc1/Cdc6 binding, the initiator makes relatively few sequence-specific contacts with DNA. However, Orc1/Cdc6 severely underwinds and bends DNA, suggesting that it relies on a mix of both DNA sequence and context-dependent DNA structural features to recognize origins. Notably, base pairing is maintained in the distorted DNA duplex upon Orc1/Cdc6 binding in the crystal structures, whereas biochemical studies have yielded contradictory findings as to whether archaeal initiators can melt DNA similarly to bacterial DnaA. Although the evolutionary kinship of archaeal and eukaryotic initiators and replicative helicases indicates that archaeal MCM is likely loaded onto duplex DNA (see next section), the temporal order of origin melting and helicase loading, as well as the mechanism for origin DNA melting, in archaeal systems remains therefore to be clearly established. Likewise, how exactly the MCM helicase is loaded onto DNA needs to be addressed in future studies.

Eukaryotic

In eukaryotes, the budding yeast Saccharomyces cerevisiae were first identified by their ability to support the replication of mini-chromosomes or plasmids, giving rise to the name Autonomously replicating sequences or ARS elements. Each budding yeast origin consists of a short (~11 bp) essential DNA sequence (called the ARS consensus sequence or ACS) that recruits replication proteins.

In other eukaryotes, including humans, the base pair sequences at the replication origins vary. Despite this sequence variation, all the origins form a base for assembly of a group of proteins known collectively as the pre-replication complex (pre-RC):

First, the origin DNA is bound by the origin recognition complex (ORC) which, with help from two further protein factors (Cdc6 and Cdt1), load the mini chromosome maintenance (or MCM) protein complex.
Once assembled, this complex of proteins indicates that the replication origin is ready for activation. Once the replication origin is activated, the cell's DNA will be replicated.

In metazoans, pre-RC formation is inhibited by the protein geminin, which binds to and inactivates Cdt1. Regulation of replication prevents the DNA from being replicated more than once each cell cycle.

In humans an origin of replication has been originally identified near the Lamin B2 gene on chromosome 19 and the ORC binding to it has extensively been studied.

Viral

Viruses often possess a single origin of replication.

A variety of proteins have been described as being involved in viral replication. For instance, Polyoma viruses utilize host cell DNA polymerases, which attach to a viral origin of replication if the T antigen is present.

References

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Wanrooij S, Miralles Fusté J, Stewart JB, Wanrooij PH, Samuelsson T, Larsson NG, Gustafsson CM, Falkenberg M (December 2012). "In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication". EMBO Reports. 13 (12): 1130–7. doi:10.1038/embor.2012.161. PMC 3513414. PMID 23090476.
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