Editing Origin of replication (section)

== Archaeal ==
[[file:Origins of DNA replication Figure 3.jpg|thumb|300px|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|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);<ref name="#10864870">{{cite journal | vauthors = Myllykallio H, Lopez P, López-García P, Heilig R, Saurin W, Zivanovic Y, Philippe H, Forterre P | display-authors = 6 | title = Bacterial mode of replication with eukaryotic-like machinery in a hyperthermophilic archaeon | journal = Science | volume = 288 | issue = 5474 | pages = 2212–5 | date = June 2000 | pmid = 10864870 | doi = 10.1126/science.288.5474.2212 | bibcode = 2000Sci...288.2212M }}</ref><ref name="#17511521">{{cite journal | vauthors = Norais C, Hawkins M, Hartman AL, Eisen JA, Myllykallio H, Allers T | title = Genetic and physical mapping of DNA replication origins in Haloferax volcanii | journal = PLOS Genetics | volume = 3 | issue = 5 | pages = e77 | date = May 2007 | pmid = 17511521 | pmc = 1868953 | doi = 10.1371/journal.pgen.0030077 | doi-access = free }}</ref><ref name="Hawkins_2013">{{cite journal | vauthors = Hawkins M, Malla S, Blythe MJ, Nieduszynski CA, Allers T | title = Accelerated growth in the absence of DNA replication origins | journal = Nature | volume = 503 | issue = 7477 | pages = 544–547 | date = November 2013 | pmid = 24185008 | pmc = 3843117 | doi = 10.1038/nature12650 | bibcode = 2013Natur.503..544H }}</ref><ref name="#24271389">{{cite journal | vauthors = Wu Z, Liu J, Yang H, Liu H, Xiang H | title = Multiple replication origins with diverse control mechanisms in Haloarcula hispanica | journal = Nucleic Acids Research | volume = 42 | issue = 4 | pages = 2282–94 | date = February 2014 | pmid = 24271389 | pmc = 3936714 | doi = 10.1093/nar/gkt1214 }}</ref><ref name="#23991938">{{cite journal | vauthors = Pelve EA, Martens-Habbena W, Stahl DA, Bernander R | title = Mapping of active replication origins in vivo in thaum- and euryarchaeal replicons | journal = Molecular Microbiology | volume = 90 | issue = 3 | pages = 538–50 | date = November 2013 | pmid = 23991938 | doi = 10.1111/mmi.12382 | doi-access = free }}</ref><ref name="#22812406">{{cite journal | vauthors = Pelve EA, Lindås AC, Knöppel A, Mira A, Bernander R | title = Four chromosome replication origins in the archaeon Pyrobaculum calidifontis | journal = Molecular Microbiology | volume = 85 | issue = 5 | pages = 986–95 | date = September 2012 | pmid = 22812406 | doi = 10.1111/j.1365-2958.2012.08155.x | doi-access = free }}</ref><ref name="#14718164">{{cite journal | vauthors = Robinson NP, Dionne I, Lundgren M, Marsh VL, Bernander R, Bell SD | title = Identification of two origins of replication in the single chromosome of the archaeon Sulfolobus solfataricus | journal = Cell | volume = 116 | issue = 1 | pages = 25–38 | date = January 2004 | pmid = 14718164 | doi = 10.1016/s0092-8674(03)01034-1 | s2cid = 12777774 | doi-access = free }}</ref><ref name="#15107501">{{cite journal | vauthors = Lundgren M, Andersson A, Chen L, Nilsson P, Bernander R | title = Three replication origins in Sulfolobus species: synchronous initiation of chromosome replication and asynchronous termination | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 18 | pages = 7046–51 | date = May 2004 | pmid = 15107501 | pmc = 406463 | doi = 10.1073/pnas.0400656101 | bibcode = 2004PNAS..101.7046L | doi-access = free }}</ref><ref name=":13" /> yet, archaeal origins also bear specialized sequence regions that control origin function.<ref name="#29357055">{{cite book | vauthors = Bell SD | title = DNA Replication | chapter = Initiation of DNA Replication in the Archaea | series = Advances in Experimental Medicine and Biology | volume = 1042 | pages = 99–115 | pmid = 29357055 | doi = 10.1007/978-981-10-6955-0_5 | year = 2017 | isbn = 978-981-10-6954-3 }}</ref><ref name="#28146124">{{cite journal | vauthors = Ausiannikava D, Allers T | title = Diversity of DNA Replication in the Archaea | journal = Genes | volume = 8 | issue = 2 | pages = 56 | date = January 2017 | pmid = 28146124 | pmc = 5333045 | doi = 10.3390/genes8020056 | doi-access = free }}</ref><ref name="#24808892">{{cite journal | vauthors = Wu Z, Liu J, Yang H, Xiang H | title = DNA replication origins in archaea | journal = Frontiers in Microbiology | volume = 5 | pages = 179 | pmid = 24808892 | pmc = 4010727 | doi = 10.3389/fmicb.2014.00179 | year = 2014 | doi-access = free }}</ref> 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.<ref name="#14718164" /><ref name="#11562464">{{cite journal | vauthors = Matsunaga F, Forterre P, Ishino Y, Myllykallio H | title = In vivo interactions of archaeal Cdc6/Orc1 and minichromosome maintenance proteins with the replication origin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11152–7 | date = September 2001 | pmid = 11562464 | pmc = 58699 | doi = 10.1073/pnas.191387498 | bibcode = 2001PNAS...9811152M | doi-access = free }}</ref> 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 in a single species.<ref name="#17511521" /><ref name="#14718164" /><ref name="#22978470">{{cite journal | vauthors = Wu Z, Liu H, Liu J, Liu X, Xiang H | title = Diversity and evolution of multiple orc/cdc6-adjacent replication origins in haloarchaea | journal = BMC Genomics | volume = 13 | pages = 478 | date = September 2012 | pmid = 22978470 | pmc = 3528665 | doi = 10.1186/1471-2164-13-478 | doi-access = free }}</ref> 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.<ref name="#14718164" /><ref name="#22918580">{{cite book | vauthors = Bell SD | chapter = Archaeal Orc1/Cdc6 Proteins | title = The Eukaryotic Replisome: A Guide to Protein Structure and Function | volume = 62 | pages = 59–69 | pmid = 22918580 | doi = 10.1007/978-94-007-4572-8_4 | series = Subcellular Biochemistry | year = 2012 | isbn = 978-94-007-4571-1 }}</ref><ref name="#23375370">{{cite journal | vauthors = Samson RY, Xu Y, Gadelha C, Stone TA, Faqiri JN, Li D, Qin N, Pu F, Liang YX, She Q, Bell SD | display-authors = 6 | title = Specificity and function of archaeal DNA replication initiator proteins | journal = Cell Reports | volume = 3 | issue = 2 | pages = 485–96 | date = February 2013 | pmid = 23375370 | pmc = 3607249 | doi = 10.1016/j.celrep.2013.01.002 }}</ref><ref name="#16978641">{{cite journal | vauthors = Grainge I, Gaudier M, Schuwirth BS, Westcott SL, Sandall J, Atanassova N, Wigley DB | title = Biochemical analysis of a DNA replication origin in the archaeon Aeropyrum pernix | journal = Journal of Molecular Biology | volume = 363 | issue = 2 | pages = 355–69 | date = October 2006 | pmid = 16978641 | doi = 10.1016/j.jmb.2006.07.076 }}</ref> In ''[[Sulfolobus solfataricus]]'', for example, three chromosomal origins have been mapped (oriC1, oriC2, and oriC3), and biochemical studies have revealed complex binding patterns of initiators at these sites.<ref name="#14718164" /><ref name="#15107501" /><ref name="#17392430">{{cite journal | vauthors = Robinson NP, Bell SD | title = Extrachromosomal element capture and the evolution of multiple replication origins in archaeal chromosomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 14 | pages = 5806–11 | date = April 2007 | pmid = 17392430 | pmc = 1851573 | doi = 10.1073/pnas.0700206104 | bibcode = 2007PNAS..104.5806R | doi-access = free }}</ref><ref name="#17255945">{{cite journal | vauthors = Robinson NP, Blood KA, McCallum SA, Edwards PA, Bell SD | title = Sister chromatid junctions in the hyperthermophilic archaeon Sulfolobus solfataricus | journal = The EMBO Journal | volume = 26 | issue = 3 | pages = 816–24 | date = February 2007 | pmid = 17255945 | pmc = 1794387 | doi = 10.1038/sj.emboj.7601529 }}</ref> The cognate initiator for oriC1 is Orc1-1, which associates with several ORBs at this origin.<ref name="#14718164" /><ref name="#23375370" /> OriC2 and oriC3 are bound by both Orc1-1 and Orc1-3.<ref name="#14718164" /><ref name="#23375370" /><ref name="#17255945" /> Conversely, a third paralog, Orc1-2, footprints at all three origins but has been postulated to negatively regulate replication initiation.<ref name="#14718164" /><ref name="#17255945" /> 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''.<ref name="#23375370" /><ref name="#17392430" /> 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;<ref name="#16978641" /><ref name="#17761879">{{cite journal | vauthors = Dueber EL, Corn JE, Bell SD, Berger JM | title = Replication origin recognition and deformation by a heterodimeric archaeal Orc1 complex | journal = Science | volume = 317 | issue = 5842 | pages = 1210–3 | date = August 2007 | pmid = 17761879 | doi = 10.1126/science.1143690 | bibcode = 2007Sci...317.1210D | s2cid = 45665434 }}</ref> 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.<ref name="Ekundayo et al"/>
       
Structural studies have provided insights into how archaeal Orc1/Cdc6 recognizes ORB elements and remodels origin DNA.<ref name="#17761879" /><ref name="#17761880">{{cite journal | vauthors = Gaudier M, Schuwirth BS, Westcott SL, Wigley DB | title = Structural basis of DNA replication origin recognition by an ORC protein | journal = Science | volume = 317 | issue = 5842 | pages = 1213–6 | date = August 2007 | pmid = 17761880 | doi = 10.1126/science.1143664 | bibcode = 2007Sci...317.1213G | s2cid = 1090383 | doi-access =  }}</ref> Orc1/Cdc6 paralogs are two-domain proteins and are composed of a AAA+ ATPase module fused to a C-terminal winged-helix fold.<ref name="#15358831">{{cite journal | vauthors = Capaldi SA, Berger JM | title = Biochemical characterization of Cdc6/Orc1 binding to the replication origin of the euryarchaeon Methanothermobacter thermoautotrophicus | journal = Nucleic Acids Research | volume = 32 | issue = 16 | pages = 4821–32 | pmid = 15358831 | pmc = 519113 | doi = 10.1093/nar/gkh819 | year = 2004 }}</ref><ref name="#11030343">{{cite journal | vauthors = Liu J, Smith CL, DeRyckere D, DeAngelis K, Martin GS, Berger JM | title = Structure and function of Cdc6/Cdc18: implications for origin recognition and checkpoint control | journal = Molecular Cell | volume = 6 | issue = 3 | pages = 637–48 | date = September 2000 | pmid = 11030343 | doi = 10.1016/s1097-2765(00)00062-9 | doi-access = free }}</ref><ref name="#15465044">{{cite journal | vauthors = Singleton MR, Morales R, Grainge I, Cook N, Isupov MN, Wigley DB | title = Conformational changes induced by nucleotide binding in Cdc6/ORC from Aeropyrum pernix | journal = Journal of Molecular Biology | volume = 343 | issue = 3 | pages = 547–57 | date = October 2004 | pmid = 15465044 | doi = 10.1016/j.jmb.2004.08.044 }}</ref> 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.<ref name="#17761879" /><ref name="#17761880" /> 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.<ref name="#17761879" /><ref name="#17761880" /> Interestingly, the DUE-flanking ORB or miniORB elements often have opposite polarities,<ref name="#17511521" /><ref name="#14718164" /><ref name="#16978641" /><ref name="#12612604">{{cite journal | vauthors = Matsunaga F, Norais C, Forterre P, Myllykallio H | title = Identification of short 'eukaryotic' Okazaki fragments synthesized from a prokaryotic replication origin | journal = EMBO Reports | volume = 4 | issue = 2 | pages = 154–8 | date = February 2003 | pmid = 12612604 | pmc = 1315830 | doi = 10.1038/sj.embor.embor732 }}</ref><ref name="#14526006">{{cite journal | vauthors = Berquist BR, DasSarma S | title = An archaeal chromosomal autonomously replicating sequence element from an extreme halophile, Halobacterium sp. strain NRC-1 | journal = Journal of Bacteriology | volume = 185 | issue = 20 | pages = 5959–66 | date = October 2003 | pmid = 14526006 | pmc = 225043 | doi = 10.1128/jb.185.20.5959-5966.2003 }}</ref> 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.<ref name="#17761879" /><ref name="#17761880" /> Since both regions of Orc1/Cdc6 associate with a minichromosome maintenance (MCM) replicative helicase,<ref name="#16150924">{{cite journal | vauthors = Kasiviswanathan R, Shin JH, Kelman Z | title = Interactions between the archaeal Cdc6 and MCM proteins modulate their biochemical properties | journal = Nucleic Acids Research | volume = 33 | issue = 15 | pages = 4940–50 | pmid = 16150924 | pmc = 1201339 | doi = 10.1093/nar/gki807 | year = 2005 }}</ref><ref name="#26725007">{{cite journal | vauthors = Samson RY, Abeyrathne PD, Bell SD | title = Mechanism of Archaeal MCM Helicase Recruitment to DNA Replication Origins | journal = Molecular Cell | volume = 61 | issue = 2 | pages = 287–96 | date = January 2016 | pmid = 26725007 | pmc = 4724246 | doi = 10.1016/j.molcel.2015.12.005 }}</ref> this specific arrangement of ORB elements and Orc1/Cdc6 is likely important for loading two MCM complexes symmetrically onto the DUE.<ref name="#14718164" /> Surprisingly, while the ORB DNA sequence determines the directionality of Orc1/Cdc6 binding, the initiator makes relatively few sequence-specific contacts with DNA.<ref name="#17761879" /><ref name="#17761880" /> 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.<ref name="#17761879" /><ref name="#17761880" /><ref name="#21227921">{{cite journal | vauthors = Dueber EC, Costa A, Corn JE, Bell SD, Berger JM | title = Molecular determinants of origin discrimination by Orc1 initiators in archaea | journal = Nucleic Acids Research | volume = 39 | issue = 9 | pages = 3621–31 | date = May 2011 | pmid = 21227921 | pmc = 3089459 | doi = 10.1093/nar/gkq1308 }}</ref> Notably, base pairing is maintained in the distorted DNA duplex upon Orc1/Cdc6 binding in the crystal structures,<ref name="#17761879" /><ref name="#17761880" /> whereas biochemical studies have yielded contradictory findings as to whether archaeal initiators can melt DNA similarly to bacterial DnaA.<ref name="#23375370" /><ref name="#16978641" /><ref name="#19787415">{{cite journal | vauthors = Matsunaga F, Takemura K, Akita M, Adachi A, Yamagami T, Ishino Y | title = Localized melting of duplex DNA by Cdc6/Orc1 at the DNA replication origin in the hyperthermophilic archaeon Pyrococcus furiosus | journal = Extremophiles | volume = 14 | issue = 1 | pages = 21–31 | date = January 2010 | pmid = 19787415 | doi = 10.1007/s00792-009-0284-9 | s2cid = 21336802 }}</ref> 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.<ref name="Ekundayo et al"/>