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== Eukaryotic == == Eukaryotic ==
]
In ], the ] ''Saccharomyces cerevisiae'' were first identified by their ability to support the replication of mini-chromosomes or ], giving rise to the name ]s or ARS elements. Each ] origin consists of a short (~11 ]) essential DNA sequence (called the ARS consensus sequence or ACS) that recruits replication proteins.{{citation needed|date=February 2016}}


Origin organization, specification, and activation in eukaryotes are more complex than in bacterial or archaeal kingdoms and significantly deviate from the paradigm established for prokaryotic replication initiation. The large genome sizes of eukaryotic cells, which range from 12 Mbp in ''S. cerevisiae'' to 3 Gbp in humans, necessitates that DNA replication starts at several hundred (in budding yeast) to tens of thousands (in humans) origins to complete DNA replication of all chromosomes during each cell cycle (for recent reviews, see <ref name="#25999062" /><ref name="#29357052">{{Cite pmid|29357052}}</ref>). With the exception of ''S. cerevisiae'' and related ''Saccharomycotina'' species, eukaryotic origins do not contain consensus DNA sequence elements but their location is influenced by contextual cues such as local DNA topology, DNA structural features, and chromatin environment.<ref name="#15459665" /><ref name="#27867195" /><ref name="#27542827" /> Nonetheless, eukaryotic origin function still relies on a conserved initiator protein complex to load replicative helicases onto DNA during the late M and ] phases of the cell cycle, a step known as origin licensing ('''Figure 1B''').<ref name="#28209641">{{Cite pmid|28209641}}</ref> In contrast to their bacterial counterparts, replicative helicases in eukaryotes are loaded onto origin duplex DNA in an inactive, double-hexameric form and only a subset of them (10-20% in mammalian cells) is activated during any given ], events that are referred to as origin firing ('''Figure 1B''').<ref name="#21282109">{{Cite pmid|21282109}}</ref><ref name="#19896182">{{Cite pmid|19896182}}</ref><ref name="#19910535">{{Cite pmid|19910535}}</ref> The location of active eukaryotic origins is therefore determined on at least two different levels, origin licensing to mark all potential origins, and origin firing to select a subset that permits assembly of the replication machinery and initiation of DNA synthesis. The extra licensed origins serve as backup and are activated only upon slowing or stalling of nearby replication forks, ensuring that DNA replication can be completed when cells encounter replication stress.<ref name="#18079179">{{Cite pmid|18079179}}</ref><ref name="#18579778">{{Cite pmid|18579778}}</ref> Together, the excess of licensed origins and the tight cell cycle control of origin licensing and firing embody two important strategies to prevent under- and overreplication and to maintain the integrity of eukaryotic genomes.
In other ], 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-RC):{{citation needed|date=February 2016}}
* First, the origin DNA is bound by the ] (ORC) which, with help from two further protein factors (] and ]), load the ] (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.


Early studies in ''S. cerevisiae'' indicated that replication origins in eukaryotes might be recognized in a DNA-sequence-specific manner analogously to those in prokaryotes. In budding yeast, the search for genetic replicators lead to the identification of autonomously replicating sequences (ARS) that support efficient DNA replication initiation of extrachromosomal DNA.<ref name="#388229">{{Cite pmid|388229}}</ref><ref name="#3311385">{{Cite pmid|3311385}}</ref><ref name="#2822257">{{Cite pmid|2822257}}</ref> These ARS regions are approximately 100-200 bp long and exhibit a multipartite organization, containing A, B1, B2, and sometimes B3 elements that together are essential for origin function ('''Figure 4''').<ref name="#1536007">{{Cite pmid|1536007}}</ref><ref name="#7935478">{{Cite pmid|7935478}}</ref> The A element encompasses the conserved 11 bp ARS consensus sequence (ACS),<ref name="#6345070">{{Cite pmid|6345070}}</ref><ref name="#6392851">{{Cite pmid|6392851}}</ref> which, in conjunction with the B1 element, constitutes the primary binding site for the heterohexameric origin recognition complex (ORC), the eukaryotic replication initiator.<ref name="#7892251">{{Cite pmid|7892251}}</ref><ref name="#7781615">{{Cite pmid|7781615}}</ref><ref name="#1579162">{{Cite pmid|1579162}}</ref><ref name="#29973722">{{Cite pmid|29973722}}</ref> Within ORC, five subunits are predicated on conserved AAA+ ATPase and winged-helix folds and co-assemble into a pentameric ring that encircles DNA ('''Figure 4''').<ref name="#29973722" /><ref name="#25762138">{{Cite pmid|25762138}}</ref><ref name="#23851460">{{Cite pmid|23851460}}</ref> In budding yeast ORC, DNA binding elements in the ATPase and winged-helix domains, as well as adjacent basic patch regions in some of the ORC subunits, are positioned in the central pore of the ORC ring such that they aid the DNA-sequence-specific recognition of the ACS in an ATP-dependent manner.<ref name="#29973722" /><ref name="#26456755">{{Cite pmid|26456755}}</ref> By contrast, the roles of the B2 and B3 elements are less clear. The B2 region is similar to the ACS in sequence and has been suggested to function as a second ORC binding site under certain conditions, or as a binding site for the replicative helicase core.<ref name="#3284655">{{Cite pmid|3284655}}</ref><ref name="#11756674">{{Cite pmid|11756674}}</ref><ref name="#28729513">{{Cite pmid|28729513}}</ref><ref name="#10757793">{{Cite pmid|10757793}}</ref><ref name="#11172708">{{Cite pmid|11172708}}</ref> Conversely, the B3 element recruits the transcription factor Abf1, albeit B3 is not found at all budding yeast origins and Abf1 binding does not appear to be strictly essential for origin function.<ref name="#1536007" /><ref name="#1579168">{{Cite pmid|1579168}}</ref><ref name="#3281162">{{Cite pmid|3281162}}</ref>
In ], pre-RC formation is inhibited by the protein ], which binds to and inactivates Cdt1. Regulation of replication prevents the DNA from being replicated more than once each ].{{citation needed|date=February 2016}}


Origin recognition in eukaryotes other than ''S. cerevisiae'' or its close relatives does not conform to the sequence-specific read-out of conserved origin DNA elements. Pursuits to isolate specific chromosomal replicator sequences more generally in eukaryotic species, either genetically or by genome-wide mapping of initiator binding or replication start sites, have failed to identify clear consensus sequences at origins.<ref name="#27436900">{{Cite pmid|27436900}}</ref><ref name="#19996087">{{Cite pmid|19996087}}</ref><ref name="#21177973">{{Cite pmid|21177973}}</ref><ref name="#23187890">{{Cite pmid|23187890}}</ref><ref name="#26560631">{{Cite pmid|26560631}}</ref><ref name="#21750104">{{Cite pmid|21750104}}</ref><ref name="#21148149">{{Cite pmid|21148149}}</ref><ref name="#17304213">{{Cite pmid|17304213}}</ref><ref name="#21813623">{{Cite pmid|21813623}}</ref><ref name="#28009254">{{Cite pmid|28009254}}</ref><ref name="#28112731">{{Cite pmid|28112731}}</ref><ref name="#22751019">{{Cite pmid|22751019}}</ref> Thus, sequence-specific DNA-initiator interactions in budding yeast signify a specialized mode for origin recognition in this system rather than an archetypal mode for origin specification across the eukaryotic domain. Nonetheless, DNA replication does initiate at discrete sites that are not randomly distributed across eukaryotic genomes, arguing that alternative means determine the chromosomal location of origins in these systems. These mechanisms involve a complex interplay between DNA accessibility, nucleotide sequence skew (both AT-richness and CpG islands have been linked to origins), ] positioning, ] features, DNA topology and certain DNA structural features (e.g., G4 motifs), as well as regulatory proteins and transcriptional interference.<ref name="#23838439" /><ref name="#25860614" /><ref name="#21364325" /><ref name="#27867195" /><ref name="#27542827" /> <ref name="#9545253">{{Cite pmid|9545253}}</ref><ref name="#19360092">{{Cite pmid|19360092}}</ref><ref name="#21750104">{{Cite pmid|21750104}}</ref><ref name="#30718387">{{Cite pmid|30718387}}</ref> Importantly, origin properties vary not only between different origins in an organism and among species, but some can also change during development and cell differentiation. The chorion locus in ''Drosophila'' follicle cells constitutes a well-established example for spatial and developmental control of initiation events. This region undergoes DNA-replication-dependent gene amplification at a defined stage during oogenesis and relies on the timely and specific activation of chorion origins, which in turn is regulated by origin-specific cis-elements and several protein factors, including the Myb complex, E2F1, and E2F2.<ref name="#10541550">{{Cite pmid|10541550}}</ref><ref name="#12490953">{{Cite pmid|12490953}}</ref><ref name="#15256498">{{Cite pmid|15256498}}</ref><ref name="#15545624">{{Cite pmid|15545624}}</ref><ref name="#11231579">{{Cite pmid|11231579}}</ref> This combinatorial specification and multifactorial regulation of metazoan origins has complicated the identification of unifying features that determine the location of replication start sites across eukaryotes more generally.
In ] 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.<ref name="human ori">], Giacca M. , '',1994;94(2–3):255-66</ref>

To facilitate replication initiation and origin recognition, ORC assemblies from various species have evolved specialized auxiliary domains that are thought to aid initiator targeting to chromosomal origins or chromosomes in general ('''Figure 4'''). For example, the Orc4 subunit in ''S. pombe'' ORC contains several AT-hooks that preferentially bind AT-rich DNA,<ref name="#10077566">{{Cite pmid|10077566}}</ref> while in metazoan ORC the TFIIB-like domain of Orc6 is thought to perform a similar function.<ref name="#17283052">{{Cite pmid|17283052}}</ref> Metazoan Orc1 proteins also harbor a bromo-adjacent homology (BAH) domain that interacts with H4K20me2-nucleosomes.<ref name="#22398447">{{Cite pmid|22398447}}</ref> Particularly in mammalian cells, H4K20 methylation has been reported to be required for efficient replication initiation, and the Orc1-BAH domain facilitates ORC association with chromosomes and Epstein-Barr virus origin-dependent replication.<ref name="#20953199">{{Cite pmid|20953199}}</ref><ref name="#23152447">{{Cite pmid|23152447}}</ref><ref name="#28778956">{{Cite pmid|28778956}}</ref><ref name="#30209253">{{Cite pmid|30209253}}</ref><ref name="#17066079">{{Cite pmid|17066079}}</ref> Therefore, it is intriguing to speculate that both observations are mechanistically linked at least in a subset of metazoa, but this possibility needs to be further explored in future studies. In addition to the recognition of certain DNA or epigenetic features, ORC also associates directly or indirectly with several partner proteins that could aid initiator recruitment, including LRWD1, PHIP (or DCAF14), HMGA1a, among others ('''Figure 4''').<ref name="#20932478" /><ref name="#22645314">{{Cite pmid|22645314}}</ref><ref name="#27924004">{{Cite pmid|27924004}}</ref><ref name="#21029866">{{Cite pmid|21029866}}</ref><ref name="#20850016">{{Cite pmid|20850016}}</ref><ref name="#26496610">{{Cite pmid|26496610}}</ref><ref name="#18234858">{{Cite pmid|18234858}}</ref><ref name="#27272143">{{Cite pmid|27272143}}</ref> Interestingly, ''Drosophila'' ORC, like its budding yeast counterpart, bends DNA and negative supercoiling has been reported to enhance DNA binding of this complex, suggesting that DNA shape and malleability might influence the location of ORC binding sites across metazoan genomes.<ref name="#14765124" /><ref name="#29973722" /><ref name="#29899147">{{Cite pmid|29899147}}</ref><ref name="#18824234">{{Cite pmid|18824234}}</ref><ref name="#9372948">{{Cite pmid|9372948}}</ref> A molecular understanding for how ORC’s DNA binding regions might support the read out of structural properties of the DNA duplex in metazoans rather than of specific DNA sequences as in ''S. cerevisiae'' awaits high-resolution structural information of DNA-bound metazoan initiator assemblies. Likewise, whether and how different epigenetic factors contribute to initiator recruitment in metazoan systems is poorly defined and is an important question that needs to be addressed in more detail.

Once recruited to origins, ORC and its co-factors Cdc6 and Cdt1 drive the deposition of the ] (Mcm2-7) complex onto DNA (for reviews see <ref name="#28209641" /><ref name="#28717046">{{Cite pmid|28717046}}</ref>). Like the archaeal replicative helicase core, Mcm2-7 is loaded as a head-to-head double hexamer onto DNA to license origins ('''Figure 1B''').<ref name="#21282109" /><ref name="#19896182" /><ref name="#19910535" /> In S-phase, Dbf4-dependent kinase (DDK) and ] (CDK) phosphorylate several Mcm2-7 subunits and additional initiation factors to promote the recruitment of the helicase co-activators Cdc45 and GINS, DNA melting, and ultimately bidirectional replisome assembly at a subset of the licensed origins ('''Figure 1B''').<ref name="#25308420">{{Cite pmid|25308420}}</ref><ref name="#28094588">{{Cite pmid|28094588}}</ref> In both yeast and metazoans, origins are free or depleted of nucleosomes, a property that is crucial for Mcm2-7 loading, indicating that chromatin state at origins regulates not only initiator recruitment but also helicase loading.<ref name="#21148149" /><ref name="#20824081">{{Cite pmid|20824081}}</ref><ref name="#20351051">{{Cite pmid|20351051}}</ref><ref name="#28322723">{{Cite pmid|28322723}}</ref><ref name="#20129055">{{Cite pmid|20129055}}</ref><ref name="#26227968">{{Cite pmid|26227968}}</ref> A permissive chromatin environment is further important for origin activation and has been implicated in regulating both origin efficiency and the timing of origin firing. Euchromatic origins typically contain active chromatin marks, replicate early, and are more efficient than late-replicating, ] origins, which conversely are characterized by repressive marks.<ref name="#29357052" /><ref name="#28322723" /><ref name="#29357061">{{Cite pmid|29357061}}</ref> Not surprisingly, several ] and ] have been found to associate with origins and certain initiation factors,<ref name="#29357053">{{Cite pmid|29357053}}</ref><ref name="#23751185">{{Cite pmid|23751185}}</ref> but how their activities impact different replication initiation events remains largely obscure. Remarkably, cis-acting “early replication control elements” (ECREs) have recently also been identified to help regulate replication timing and to influence 3D genome architecture in mammalian cells.<ref name="#30595451">{{Cite pmid|30595451}}</ref> Understanding the molecular and biochemical mechanisms that orchestrate this complex interplay between 3D genome organization, local and higher-order chromatin structure, and replication initiation is an exciting topic for further studies.

Why have metazoan replication origins diverged from the DNA sequence-specific recognition paradigm that determines replication start sites in prokaryotes and budding yeast? Observations that metazoan origins often co-localize with promoter regions in ''Drosophila'' and mammalian cells and that replication-transcription conflicts due to collisions of the underlying molecular machineries can lead to DNA damage suggest that proper coordination of transcription and replication is important for maintaining genome stability.<ref name="#19996087" /><ref name="#23187890" /><ref name="#21750104" /><ref name="#21813623" /><ref name="#18838675">{{Cite pmid|18838675}}</ref><ref name="#8638128">{{Cite pmid|8638128}}</ref><ref name="#27362223">{{Cite pmid|27362223}}</ref><ref name="#19560424">{{Cite pmid|19560424}}</ref> Recent findings also point to a more direct role of transcription in influencing the location of origins, either by inhibiting Mcm2-7 loading or by repositioning of loaded Mcm2-7 on chromosomes.<ref name="#26656162">{{Cite pmid|26656162}}</ref><ref name="#30718387">{{Cite pmid|30718387}}</ref> Sequence-independent (but not necessarily random) initiator binding to DNA additionally allows for flexibility in specifying helicase loading sites and, together with transcriptional interference and the variability in activation efficiencies of licensed origins, likely determines origin location and contributes to the co-regulation of DNA replication and transcriptional programs during development and cell fate transitions. Computational modeling of initiation events in ''S. pombe'', as well as the identification of cell-type specific and developmentally-regulated origins in metazoans, are in agreement with this notion.<ref name="#21177973" /><ref name="#28112731" /><ref name="#21258320">{{Cite pmid|21258320}}</ref><ref name="#27168766">{{Cite pmid|27168766}}</ref><ref name="#22090375">{{Cite pmid|22090375}}</ref><ref name="#25921534">{{Cite pmid|25921534}}</ref><ref name="#9499407">{{Cite pmid|9499407}}</ref><ref name="#30718387">{{Cite pmid|30718387}}</ref> However, a large degree of flexibility in origin choice also exists among different cells within a single population,<ref name="#21750104" /><ref name="#22751019" /><ref name="#27168766" /> albeit the molecular mechanisms that lead to the heterogeneity in origin usage remain ill-defined. Mapping origins in single cells in metazoan systems and correlating these initiation events with single-cell gene expression and chromatin status will be important to elucidate whether origin choice is purely stochastic or controlled in a defined manner.


== Viral== == Viral==

Revision as of 03:58, 14 September 2019

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

Template:Figure Origin organization and recognition in bacteria. A) Schematic of the architecture of E. coli origin oriC, Thermotoga maritima oriC, and the bipartite origin in Helicobacter pylori. The DUE is flanked on one side by several high- and weak-affinity DnaA-boxes as indicated for E. coli oriC. B) Domain organization of the E. coli initiator DnaA. Magenta circle indicates the single-strand DNA binding site. C) Models for origin recognition and melting by DnaA. In the two-state model (left panel), the DnaA protomers transition from a dsDNA binding mode (mediated by the HTH-domains recognizing DnaA-boxes) to an ssDNA binding mode (mediated by the AAA+ domains). In the loop-back model, the DNA is sharply bent backwards onto the DnaA filament (facilitated by the regulatory protein IHF) so that a single protomer binds both duplex and single-stranded regions. In either instance, the DnaA filament melts the DNA duplex and stabilizes the initiation bubble prior to loading of the replicative helicase (DnaB in E. coli). HTH – helix-turn-helix domain, DUE – DNA unwinding element, IHF – integration host factor.

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

Template:Figure Origin organization and recognition in archaea. A) The circular chromosome of Sulfolobus solfataricus contains three different origins. B) Arrangement of initiator binding sites at two S. solfataricus origins, oriC1 and oriC2. Orc1-1 association with ORB elements is shown for oriC1. Recognition elements for additional Orc1/Cdc6 paralogs are also indicated, while WhiP binding sites have been omitted. C) Domain architecture of archaeal Orc1/Cdc6 paralogs. The orientation of ORB elements at origins leads to directional binding of Orc1/Cdc6 and MCM loading in between opposing ORBs (in B). (m)ORB – (mini-)origin recognition box, DUE – DNA unwinding element, WH – winged-helix domain.

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

Template:Figure Origin organization and recognition in eukaryotes. Specific DNA elements and epigenetic features involved in ORC recruitment and origin function are summarized for S. cerevisiae, S. pombe, and metazoan origins. A schematic of the ORC architecture is also shown, highlighting the arrangement of the AAA+ and winged-helix domains into a pentameric ring that encircles origin DNA. Ancillary domains of several ORC subunits involved in targeting ORC to origins are included. Other regions in ORC subunits may also be involved in initiator recruitment, either by directly or indirectly associating with partner proteins. A few examples are listed. Note that the BAH domain in S. cerevisiae Orc1 binds nucleosomes but does not recognize H4K20me2. BAH – bromo-adjacent homology domain, WH – winged-helix domain, TFIIB – transcription factor II B-like domain in Orc6, G4 – G quadruplex, OGRE – origin G-rich repeated element.

Origin organization, specification, and activation in eukaryotes are more complex than in bacterial or archaeal kingdoms and significantly deviate from the paradigm established for prokaryotic replication initiation. The large genome sizes of eukaryotic cells, which range from 12 Mbp in S. cerevisiae to 3 Gbp in humans, necessitates that DNA replication starts at several hundred (in budding yeast) to tens of thousands (in humans) origins to complete DNA replication of all chromosomes during each cell cycle (for recent reviews, see ). With the exception of S. cerevisiae and related Saccharomycotina species, eukaryotic origins do not contain consensus DNA sequence elements but their location is influenced by contextual cues such as local DNA topology, DNA structural features, and chromatin environment. Nonetheless, eukaryotic origin function still relies on a conserved initiator protein complex to load replicative helicases onto DNA during the late M and G1 phases of the cell cycle, a step known as origin licensing (Figure 1B). In contrast to their bacterial counterparts, replicative helicases in eukaryotes are loaded onto origin duplex DNA in an inactive, double-hexameric form and only a subset of them (10-20% in mammalian cells) is activated during any given S phase, events that are referred to as origin firing (Figure 1B). The location of active eukaryotic origins is therefore determined on at least two different levels, origin licensing to mark all potential origins, and origin firing to select a subset that permits assembly of the replication machinery and initiation of DNA synthesis. The extra licensed origins serve as backup and are activated only upon slowing or stalling of nearby replication forks, ensuring that DNA replication can be completed when cells encounter replication stress. Together, the excess of licensed origins and the tight cell cycle control of origin licensing and firing embody two important strategies to prevent under- and overreplication and to maintain the integrity of eukaryotic genomes.

Early studies in S. cerevisiae indicated that replication origins in eukaryotes might be recognized in a DNA-sequence-specific manner analogously to those in prokaryotes. In budding yeast, the search for genetic replicators lead to the identification of autonomously replicating sequences (ARS) that support efficient DNA replication initiation of extrachromosomal DNA. These ARS regions are approximately 100-200 bp long and exhibit a multipartite organization, containing A, B1, B2, and sometimes B3 elements that together are essential for origin function (Figure 4). The A element encompasses the conserved 11 bp ARS consensus sequence (ACS), which, in conjunction with the B1 element, constitutes the primary binding site for the heterohexameric origin recognition complex (ORC), the eukaryotic replication initiator. Within ORC, five subunits are predicated on conserved AAA+ ATPase and winged-helix folds and co-assemble into a pentameric ring that encircles DNA (Figure 4). In budding yeast ORC, DNA binding elements in the ATPase and winged-helix domains, as well as adjacent basic patch regions in some of the ORC subunits, are positioned in the central pore of the ORC ring such that they aid the DNA-sequence-specific recognition of the ACS in an ATP-dependent manner. By contrast, the roles of the B2 and B3 elements are less clear. The B2 region is similar to the ACS in sequence and has been suggested to function as a second ORC binding site under certain conditions, or as a binding site for the replicative helicase core. Conversely, the B3 element recruits the transcription factor Abf1, albeit B3 is not found at all budding yeast origins and Abf1 binding does not appear to be strictly essential for origin function.

Origin recognition in eukaryotes other than S. cerevisiae or its close relatives does not conform to the sequence-specific read-out of conserved origin DNA elements. Pursuits to isolate specific chromosomal replicator sequences more generally in eukaryotic species, either genetically or by genome-wide mapping of initiator binding or replication start sites, have failed to identify clear consensus sequences at origins. Thus, sequence-specific DNA-initiator interactions in budding yeast signify a specialized mode for origin recognition in this system rather than an archetypal mode for origin specification across the eukaryotic domain. Nonetheless, DNA replication does initiate at discrete sites that are not randomly distributed across eukaryotic genomes, arguing that alternative means determine the chromosomal location of origins in these systems. These mechanisms involve a complex interplay between DNA accessibility, nucleotide sequence skew (both AT-richness and CpG islands have been linked to origins), Nucleosome positioning, epigenetic features, DNA topology and certain DNA structural features (e.g., G4 motifs), as well as regulatory proteins and transcriptional interference. Importantly, origin properties vary not only between different origins in an organism and among species, but some can also change during development and cell differentiation. The chorion locus in Drosophila follicle cells constitutes a well-established example for spatial and developmental control of initiation events. This region undergoes DNA-replication-dependent gene amplification at a defined stage during oogenesis and relies on the timely and specific activation of chorion origins, which in turn is regulated by origin-specific cis-elements and several protein factors, including the Myb complex, E2F1, and E2F2. This combinatorial specification and multifactorial regulation of metazoan origins has complicated the identification of unifying features that determine the location of replication start sites across eukaryotes more generally.

To facilitate replication initiation and origin recognition, ORC assemblies from various species have evolved specialized auxiliary domains that are thought to aid initiator targeting to chromosomal origins or chromosomes in general (Figure 4). For example, the Orc4 subunit in S. pombe ORC contains several AT-hooks that preferentially bind AT-rich DNA, while in metazoan ORC the TFIIB-like domain of Orc6 is thought to perform a similar function. Metazoan Orc1 proteins also harbor a bromo-adjacent homology (BAH) domain that interacts with H4K20me2-nucleosomes. Particularly in mammalian cells, H4K20 methylation has been reported to be required for efficient replication initiation, and the Orc1-BAH domain facilitates ORC association with chromosomes and Epstein-Barr virus origin-dependent replication. Therefore, it is intriguing to speculate that both observations are mechanistically linked at least in a subset of metazoa, but this possibility needs to be further explored in future studies. In addition to the recognition of certain DNA or epigenetic features, ORC also associates directly or indirectly with several partner proteins that could aid initiator recruitment, including LRWD1, PHIP (or DCAF14), HMGA1a, among others (Figure 4). Interestingly, Drosophila ORC, like its budding yeast counterpart, bends DNA and negative supercoiling has been reported to enhance DNA binding of this complex, suggesting that DNA shape and malleability might influence the location of ORC binding sites across metazoan genomes. A molecular understanding for how ORC’s DNA binding regions might support the read out of structural properties of the DNA duplex in metazoans rather than of specific DNA sequences as in S. cerevisiae awaits high-resolution structural information of DNA-bound metazoan initiator assemblies. Likewise, whether and how different epigenetic factors contribute to initiator recruitment in metazoan systems is poorly defined and is an important question that needs to be addressed in more detail.

Once recruited to origins, ORC and its co-factors Cdc6 and Cdt1 drive the deposition of the minichromosome maintenance 2-7 (Mcm2-7) complex onto DNA (for reviews see ). Like the archaeal replicative helicase core, Mcm2-7 is loaded as a head-to-head double hexamer onto DNA to license origins (Figure 1B). In S-phase, Dbf4-dependent kinase (DDK) and Cyclin-dependent kinase (CDK) phosphorylate several Mcm2-7 subunits and additional initiation factors to promote the recruitment of the helicase co-activators Cdc45 and GINS, DNA melting, and ultimately bidirectional replisome assembly at a subset of the licensed origins (Figure 1B). In both yeast and metazoans, origins are free or depleted of nucleosomes, a property that is crucial for Mcm2-7 loading, indicating that chromatin state at origins regulates not only initiator recruitment but also helicase loading. A permissive chromatin environment is further important for origin activation and has been implicated in regulating both origin efficiency and the timing of origin firing. Euchromatic origins typically contain active chromatin marks, replicate early, and are more efficient than late-replicating, heterochromatic origins, which conversely are characterized by repressive marks. Not surprisingly, several chromatin remodelers and chromatin-modifying enzymes have been found to associate with origins and certain initiation factors, but how their activities impact different replication initiation events remains largely obscure. Remarkably, cis-acting “early replication control elements” (ECREs) have recently also been identified to help regulate replication timing and to influence 3D genome architecture in mammalian cells. Understanding the molecular and biochemical mechanisms that orchestrate this complex interplay between 3D genome organization, local and higher-order chromatin structure, and replication initiation is an exciting topic for further studies.

Why have metazoan replication origins diverged from the DNA sequence-specific recognition paradigm that determines replication start sites in prokaryotes and budding yeast? Observations that metazoan origins often co-localize with promoter regions in Drosophila and mammalian cells and that replication-transcription conflicts due to collisions of the underlying molecular machineries can lead to DNA damage suggest that proper coordination of transcription and replication is important for maintaining genome stability. Recent findings also point to a more direct role of transcription in influencing the location of origins, either by inhibiting Mcm2-7 loading or by repositioning of loaded Mcm2-7 on chromosomes. Sequence-independent (but not necessarily random) initiator binding to DNA additionally allows for flexibility in specifying helicase loading sites and, together with transcriptional interference and the variability in activation efficiencies of licensed origins, likely determines origin location and contributes to the co-regulation of DNA replication and transcriptional programs during development and cell fate transitions. Computational modeling of initiation events in S. pombe, as well as the identification of cell-type specific and developmentally-regulated origins in metazoans, are in agreement with this notion. However, a large degree of flexibility in origin choice also exists among different cells within a single population, albeit the molecular mechanisms that lead to the heterogeneity in origin usage remain ill-defined. Mapping origins in single cells in metazoan systems and correlating these initiation events with single-cell gene expression and chromatin status will be important to elucidate whether origin choice is purely stochastic or controlled in a defined manner.

Viral

HHV-6 genome
Genome of human herpesvirus-6, a member of the Herpesviridae family. The origin of replication is labeled as "OOR."

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.

See also

References

  1. Technical Glossary Edward K. Wagner, Martinez Hewlett, David Bloom and David Camerini Basic Virology Third Edition, Blackwell publishing, 2007 ISBN 1-4051-4715-6
  2. Hulo C, de Castro E, Masson P, Bougueleret L, Bairoch A, Xenarios I, Le Mercier P (January 2011). "ViralZone: a knowledge resource to understand virus diversity". Nucleic Acids Research. 39 (Database issue): D576-82. doi:10.1093/nar/gkq901. PMC 3013774. PMID 20947564.
  3. Martín-Parras L, Hernández P, Martínez-Robles ML, Schvartzman JB (August 1991). "Unidirectional replication as visualized by two-dimensional agarose gel electrophoresis". Journal of Molecular Biology. 220 (4): 843–53. doi:10.1016/0022-2836(91)90357-c. PMID 1880800.
  4. Yakovchuk P, Protozanova E, Frank-Kamenetskii MD (2006). "Base-stacking and base-pairing contributions into thermal stability of the DNA double helix". Nucleic Acids Research. 34 (2): 564–74. doi:10.1093/nar/gkj454. PMC 1360284. PMID 16449200.
  5. "origin of replication". wolfson.huji.ac.il. Retrieved 2019-02-05.
  6. Mott ML, Berger JM (May 2007). "DNA replication initiation: mechanisms and regulation in bacteria". Nature Reviews. Microbiology. 5 (5): 343–54. doi:10.1038/nrmicro1640. PMID 17435790.
  7. Kelman LM, Kelman Z (September 2004). "Multiple origins of replication in archaea". Trends in Microbiology. 12 (9): 399–401. doi:10.1016/j.tim.2004.07.001. PMID 15337158.
  8. Nasheuer HP, Smith R, Bauerschmidt C, Grosse F, Weisshart K (2002). Initiation of eukaryotic DNA replication: regulation and mechanisms. Vol. 72. pp. 41–94. doi:10.1016/S0079-6603(02)72067-9. ISBN 9780125400725. PMID 12206458. {{cite book}}: |journal= ignored (help)
  9. Lightowlers RN, Chrzanowska-Lightowlers ZM (December 2012). "Exploring our origins—the importance of OriL in mtDNA maintenance and replication". EMBO Reports. 13 (12): 1038–9. doi:10.1038/embor.2012.175. PMC 3512418. PMID 23146883.
  10. 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.
  11. Scotto JM, Stralin HG (December 1977). "Ultrastructure of the liver in a case of childhood cystinosis". Virchows Archiv. A, Pathological Anatomy and Histology. 377 (1): 43–8. doi:10.1007/BF00432697. PMID 146947.
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  • Lewin, Benjamin (2004). Genes VIII. Prentice Hall.

External links

DNA replication (comparing prokaryotic to eukaryotic)
Initiation
Prokaryotic
(initiation)
Eukaryotic
(preparation in
G1 phase)
Both
Replication
Prokaryotic
(elongation)
Eukaryotic
(synthesis in
S phase)
Both
Termination
Category:
Origin of replication: Difference between revisions Add topic