Editing Origin of replication (section)

== Replicon model ==
More than five decades ago, [[François Jacob|Jacob]], [[Sydney Brenner|Brenner]], and Cuzin proposed the replicon hypothesis to explain the regulation of chromosomal DNA synthesis in ''E. coli''.<ref name=":0">{{Cite journal| vauthors = Jacob F, Brenner S, Cuzin F |date=1963-01-01|title=On the Regulation of Dna Replication in Bacteria|journal=Cold Spring Harbor Symposia on Quantitative Biology|volume=28|pages=329–348|doi=10.1101/sqb.1963.028.01.048|issn=0091-7451}}</ref> The model postulates that a diffusible, ''trans''-acting factor, a so-called initiator, interacts with a ''cis''-acting DNA element, the replicator, to promote replication onset at a nearby origin. Once bound to replicators, initiators (often with the help of co-loader proteins) deposit replicative [[helicase]]s onto DNA, which subsequently drive the recruitment of additional replisome components and the assembly of the entire replication machinery. The replicator thereby specifies the location of replication initiation events, and the chromosome region that is replicated from a single origin or initiation event is defined as the replicon.<ref name="Ekundayo et al"/>

A fundamental feature of the replicon hypothesis is that it relies on positive regulation to control DNA replication onset, which can explain many experimental observations in bacterial and phage systems.<ref name=":0" /> For example, it accounts for the failure of extrachromosomal DNAs without origins to replicate when introduced into host cells. It further rationalizes plasmid incompatibilities in E. coli, where certain plasmids destabilize each other's inheritance due to competition for the same molecular initiation machinery.<ref>{{cite journal | vauthors = Novick RP | title = Plasmid incompatibility | journal = Microbiological Reviews | volume = 51 | issue = 4 | pages = 381–95 | date = December 1987 | doi = 10.1128/MMBR.51.4.381-395.1987 | pmid = 3325793 | pmc = 373122 }}</ref> By contrast, a model of negative regulation (analogous to the replicon-operator model for transcription) fails to explain the above findings.<ref name=":0" /> Nonetheless, research subsequent to Jacob's, Brenner's and Cuzin's proposal of the replicon model has discovered many additional layers of replication control in bacteria and eukaryotes that comprise both positive and negative regulatory elements, highlighting both the complexity and the importance of restricting DNA replication temporally and spatially.<ref name="Ekundayo et al"/><ref>{{cite journal | vauthors = Skarstad K, Katayama T | title = Regulating DNA replication in bacteria | journal = Cold Spring Harbor Perspectives in Biology | volume = 5 | issue = 4 | pages = a012922 | date = April 2013 | pmid = 23471435 | pmc = 3683904 | doi = 10.1101/cshperspect.a012922 }}</ref><ref name=":3">{{cite book | vauthors = Marks AB, Fu H, Aladjem MI | title = DNA Replication | chapter = Regulation of Replication Origins | series = Advances in Experimental Medicine and Biology | volume = 1042 | pages = 43–59 | date = 2017 | pmid = 29357052 | pmc = 6622447 | doi = 10.1007/978-981-10-6955-0_2 | isbn = 978-981-10-6954-3 }}</ref><ref name=":4">{{cite journal | vauthors = Parker MW, Botchan MR, Berger JM | title = Mechanisms and regulation of DNA replication initiation in eukaryotes | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 52 | issue = 2 | pages = 107–144 | date = April 2017 | pmid = 28094588 | pmc = 5545932 | doi = 10.1080/10409238.2016.1274717 }}</ref>

The concept of the replicator as a genetic entity has proven very useful in the quest to identify replicator DNA sequences and initiator proteins in [[prokaryote]]s, and to some extent also in [[eukaryote]]s, although the organization and complexity of replicators differ considerably between the domains of life.<ref name="#15459665">{{cite journal | vauthors = Gilbert DM | title = In search of the holy replicator | journal = Nature Reviews. Molecular Cell Biology | volume = 5 | issue = 10 | pages = 848–55 | date = October 2004 | pmid = 15459665 | pmc = 1255919 | doi = 10.1038/nrm1495 }}</ref><ref>{{cite journal | vauthors = Aladjem MI, Fanning E | title = The replicon revisited: an old model learns new tricks in metazoan chromosomes | journal = EMBO Reports | volume = 5 | issue = 7 | pages = 686–91 | date = July 2004 | pmid = 15229645 | pmc = 1299096 | doi = 10.1038/sj.embor.7400185 }}</ref> While bacterial genomes typically contain a single replicator that is specified by consensus DNA sequence elements and that controls replication of the entire chromosome, most eukaryotic replicators – with the exception of budding yeast – are not defined at the level of DNA sequence; instead, they appear to be specified combinatorially by local DNA structural and [[chromatin]] cues.<ref name=":6">{{cite journal | vauthors = Remus D, Beall EL, Botchan MR | title = DNA topology, not DNA sequence, is a critical determinant for Drosophila ORC-DNA binding | journal = The EMBO Journal | volume = 23 | issue = 4 | pages = 897–907 | date = February 2004 | pmid = 14765124 | pmc = 380993 | doi = 10.1038/sj.emboj.7600077 }}</ref><ref>{{cite journal | vauthors = Vashee S, Cvetic C, Lu W, Simancek P, Kelly TJ, Walter JC | title = Sequence-independent DNA binding and replication initiation by the human origin recognition complex | journal = Genes & Development | volume = 17 | issue = 15 | pages = 1894–908 | date = August 2003 | pmid = 12897055 | pmc = 196240 | doi = 10.1101/gad.1084203 }}</ref><ref name=":7">{{cite journal | vauthors = Shen Z, Sathyan KM, Geng Y, Zheng R, Chakraborty A, Freeman B, Wang F, Prasanth KV, Prasanth SG | display-authors = 6 | title = A WD-repeat protein stabilizes ORC binding to chromatin | journal = Molecular Cell | volume = 40 | issue = 1 | pages = 99–111 | date = October 2010 | pmid = 20932478 | pmc = 5201136 | doi = 10.1016/j.molcel.2010.09.021 }}</ref><ref name=":8">{{cite journal | vauthors = Dorn ES, Cook JG | title = Nucleosomes in the neighborhood: new roles for chromatin modifications in replication origin control | journal = Epigenetics | volume = 6 | issue = 5 | pages = 552–9 | date = May 2011 | pmid = 21364325 | pmc = 3230546 | doi = 10.4161/epi.6.5.15082 }}</ref><ref name=":9">{{cite journal | vauthors = Aladjem MI, Redon CE | title = Order from clutter: selective interactions at mammalian replication origins | journal = Nature Reviews. Genetics | volume = 18 | issue = 2 | pages = 101–116 | date = February 2017 | pmid = 27867195 | pmc = 6596300 | doi = 10.1038/nrg.2016.141 }}</ref><ref name=":10">{{cite journal | vauthors = Fragkos M, Ganier O, Coulombe P, Méchali M | title = DNA replication origin activation in space and time | journal = Nature Reviews. Molecular Cell Biology | volume = 16 | issue = 6 | pages = 360–74 | date = June 2015 | pmid = 25999062 | doi = 10.1038/nrm4002 | s2cid = 37108355 }}</ref><ref name=":11">{{cite journal | vauthors = Prioleau MN, MacAlpine DM | title = DNA replication origins-where do we begin? | journal = Genes & Development | volume = 30 | issue = 15 | pages = 1683–97 | date = August 2016 | pmid = 27542827 | pmc = 5002974 | doi = 10.1101/gad.285114.116 }}</ref><ref>{{cite journal | vauthors = Cayrou C, Coulombe P, Puy A, Rialle S, Kaplan N, Segal E, Méchali M | title = New insights into replication origin characteristics in metazoans | journal = Cell Cycle | volume = 11 | issue = 4 | pages = 658–67 | date = February 2012 | pmid = 22373526 | pmc = 3318102 | doi = 10.4161/cc.11.4.19097 }}</ref><ref>{{cite journal | vauthors = Lombraña R, Almeida R, Álvarez A, Gómez M | title = R-loops and initiation of DNA replication in human cells: a missing link? | journal = Frontiers in Genetics | volume = 6 | pages = 158 | date = 2015 | pmid = 25972891 | pmc = 4412123 | doi = 10.3389/fgene.2015.00158 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jang SM, Zhang Y, Utani K, Fu H, Redon CE, Marks AB, Smith OK, Redmond CJ, Baris AM, Tulchinsky DA, Aladjem MI | display-authors = 6 | title = The replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin | journal = Nature Communications | volume = 9 | issue = 1 | pages = 2782 | date = July 2018 | pmid = 30018425 | pmc = 6050238 | doi = 10.1038/s41467-018-05177-6 | bibcode = 2018NatCo...9.2782J }}</ref> Eukaryotic chromosomes are also much larger than their bacterial counterparts, raising the need for initiating DNA synthesis from many origins simultaneously to ensure timely replication of the entire genome. Additionally, many more replicative helicases are loaded than activated to initiate replication in a given cell cycle. The context-driven definition of replicators and selection of origins suggests a relaxed replicon model in eukaryotic systems that allows for flexibility in the DNA replication program.<ref name="#15459665"/> Although replicators and origins can be spaced physically apart on chromosomes, they often co-localize or are located in close proximity; for simplicity, we will thus refer to both elements as ‘origins’ throughout this review. Taken together, the discovery and isolation of origin sequences in various organisms represents a significant milestone towards gaining mechanistic understanding of replication initiation. In addition, these accomplishments had profound biotechnological implications for the development of shuttle vectors that can be propagated in bacterial, yeast and mammalian cells.<ref name="Ekundayo et al"/><ref>{{cite journal | vauthors = Zakian VA, Scott JF | title = Construction, replication, and chromatin structure of TRP1 RI circle, a multiple-copy synthetic plasmid derived from Saccharomyces cerevisiae chromosomal DNA | journal = Molecular and Cellular Biology | volume = 2 | issue = 3 | pages = 221–32 | date = March 1982 | pmid = 6287231 | pmc = 369780 | doi = 10.1128/mcb.2.3.221-232.1982 }}</ref><ref>{{cite journal | vauthors = Rhodes N, Company M, Errede B | title = A yeast-Escherichia coli shuttle vector containing the M13 origin of replication | journal = Plasmid | volume = 23 | issue = 2 | pages = 159–62 | date = March 1990 | pmid = 2194231 | doi = 10.1016/0147-619x(90)90036-c }}</ref><ref>{{cite journal | vauthors = Paululat A, Heinisch JJ | title = New yeast/E. coli/Drosophila triple shuttle vectors for efficient generation of Drosophila P element transformation constructs | journal = Gene | volume = 511 | issue = 2 | pages = 300–5 | date = December 2012 | pmid = 23026211 | doi = 10.1016/j.gene.2012.09.058 }}</ref>