Editing Origin of replication (section)

== Bacterial==
<!---Redirect from [[Oric]] article, and separate redirect from OriC, lands at this section.--->
[[file:Origins of DNA replication Figure 2.jpg|thumb|300px|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)<ref>{{cite journal | vauthors = Ryan VT, Grimwade JE, Camara JE, Crooke E, Leonard AC | title = Escherichia coli prereplication complex assembly is regulated by dynamic interplay among Fis, IHF and DnaA | journal = Molecular Microbiology | volume = 51 | issue = 5 | pages = 1347–59 | date = March 2004 | pmid = 14982629 | doi = 10.1046/j.1365-2958.2003.03906.x | s2cid = 22598422 | doi-access = free }}</ref> 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;<ref name=":12">{{cite journal | vauthors = Mackiewicz P, Zakrzewska-Czerwinska J, Zawilak A, Dudek MR, Cebrat S | title = Where does bacterial replication start? Rules for predicting the oriC region | journal = Nucleic Acids Research | volume = 32 | issue = 13 | pages = 3781–91 | date = 2004 | pmid = 15258248 | pmc = 506792 | doi = 10.1093/nar/gkh699 }}</ref><ref name=":13">{{cite journal | vauthors = Luo H, Gao F | title = DoriC 10.0: an updated database of replication origins in prokaryotic genomes including chromosomes and plasmids | journal = Nucleic Acids Research | volume = 47 | issue = D1 | pages = D74–D77 | date = January 2019 | pmid = 30364951 | pmc = 6323995 | doi = 10.1093/nar/gky1014 }}</ref> 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.<ref name=":14">{{cite journal | vauthors = Fuller RS, Funnell BE, Kornberg A | title = The dnaA protein complex with the E. coli chromosomal replication origin (oriC) and other DNA sites | journal = Cell | volume = 38 | issue = 3 | pages = 889–900 | date = October 1984 | pmid = 6091903 | doi = 10.1016/0092-8674(84)90284-8 | s2cid = 23316215 }}</ref><ref>{{cite journal | vauthors = Fuller RS, Kornberg A | title = Purified dnaA protein in initiation of replication at the Escherichia coli chromosomal origin of replication | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 19 | pages = 5817–21 | date = October 1983 | pmid = 6310593 | pmc = 390166 | doi = 10.1073/pnas.80.19.5817 | bibcode = 1983PNAS...80.5817F | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jakimowicz D, Majka J, Messer W, Speck C, Fernandez M, Martin MC, Sanchez J, Schauwecker F, Keller U, Schrempf H, Zakrzewska-Czerwińska J | display-authors = 6 | title = Structural elements of the Streptomyces oriC region and their interactions with the DnaA protein | journal = Microbiology | volume = 144 ( Pt 5) | issue = 5 | pages = 1281–90 | date = May 1998 | pmid = 9611803 | doi = 10.1099/00221287-144-5-1281 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tsodikov OV, Biswas T | title = Structural and thermodynamic signatures of DNA recognition by Mycobacterium tuberculosis DnaA | journal = Journal of Molecular Biology | volume = 410 | issue = 3 | pages = 461–76 | date = July 2011 | pmid = 21620858 | doi = 10.1016/j.jmb.2011.05.007 }}</ref> 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.<ref name=":15" /><ref>{{cite journal | vauthors = Costa A, Hood IV, Berger JM | title = Mechanisms for initiating cellular DNA replication | journal = Annual Review of Biochemistry | volume = 82 | pages = 25–54 | date = 2013 | pmid = 23746253 | pmc = 4696014 | doi = 10.1146/annurev-biochem-052610-094414 }}</ref><ref>{{cite journal | vauthors = Wolański M, Donczew R, Zawilak-Pawlik A, Zakrzewska-Czerwińska J | title = oriC-encoded instructions for the initiation of bacterial chromosome replication | journal = Frontiers in Microbiology | volume = 5 | pages = 735 | date = 2014 | pmid = 25610430 | pmc = 4285127 | doi = 10.3389/fmicb.2014.00735 | doi-access = free }}</ref> 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 proteins|AAA+]]) domain, respectively.<ref name=":17">{{cite journal | vauthors = Messer W, Blaesing F, Majka J, Nardmann J, Schaper S, Schmidt A, Seitz H, Speck C, Tüngler D, Wegrzyn G, Weigel C, Welzeck M, Zakrzewska-Czerwinska J | display-authors = 6 | title = Functional domains of DnaA proteins | journal = Biochimie | volume = 81 | issue = 8–9 | pages = 819–25 | date = 1999 | pmid = 10572294 | doi = 10.1016/s0300-9084(99)00215-1 }}</ref><ref>{{cite journal | vauthors = Sutton MD, Kaguni JM | title = The Escherichia coli dnaA gene: four functional domains | journal = Journal of Molecular Biology | volume = 274 | issue = 4 | pages = 546–61 | date = December 1997 | pmid = 9417934 | doi = 10.1006/jmbi.1997.1425 }}</ref><ref>{{cite journal | vauthors = Speck C, Messer W | title = Mechanism of origin unwinding: sequential binding of DnaA to double- and single-stranded DNA | journal = The EMBO Journal | volume = 20 | issue = 6 | pages = 1469–76 | date = March 2001 | pmid = 11250912 | pmc = 145534 | doi = 10.1093/emboj/20.6.1469 }}</ref><ref name=":18">{{cite journal | vauthors = Fujikawa N, Kurumizaka H, Nureki O, Terada T, Shirouzu M, Katayama T, Yokoyama S | title = Structural basis of replication origin recognition by the DnaA protein | journal = Nucleic Acids Research | volume = 31 | issue = 8 | pages = 2077–86 | date = April 2003 | pmid = 12682358 | pmc = 153737 | doi = 10.1093/nar/gkg309 }}</ref><ref name=":19">{{cite journal | vauthors = Duderstadt KE, Chuang K, Berger JM | title = DNA stretching by bacterial initiators promotes replication origin opening | journal = Nature | volume = 478 | issue = 7368 | pages = 209–13 | date = October 2011 | pmid = 21964332 | pmc = 3192921 | doi = 10.1038/nature10455 | bibcode = 2011Natur.478..209D }}</ref><ref name=":20">{{cite journal | vauthors = Erzberger JP, Pirruccello MM, Berger JM | title = The structure of bacterial DnaA: implications for general mechanisms underlying DNA replication initiation | journal = The EMBO Journal | volume = 21 | issue = 18 | pages = 4763–73 | date = September 2002 | pmid = 12234917 | pmc = 126292 | doi = 10.1093/emboj/cdf496 }}</ref><ref>{{cite journal | vauthors = Sutton MD, Kaguni JM | title = Threonine 435 of Escherichia coli DnaA protein confers sequence-specific DNA binding activity | journal = The Journal of Biological Chemistry | volume = 272 | issue = 37 | pages = 23017–24 | date = September 1997 | pmid = 9287298 | doi = 10.1074/jbc.272.37.23017 | doi-access = free }}</ref> 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.<ref name="Ekundayo et al"/><ref name=":12" /><ref name=":13" /><ref>{{cite journal | vauthors = Bramhill D, Kornberg A | title = A model for initiation at origins of DNA replication | journal = Cell | volume = 54 | issue = 7 | pages = 915–8 | date = September 1988 | pmid = 2843291 | doi = 10.1016/0092-8674(88)90102-x | s2cid = 1705480 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Rozgaja TA, Grimwade JE, Iqbal M, Czerwonka C, Vora M, Leonard AC | title = Two oppositely oriented arrays of low-affinity recognition sites in oriC guide progressive binding of DnaA during Escherichia coli pre-RC assembly | journal = Molecular Microbiology | volume = 82 | issue = 2 | pages = 475–88 | date = October 2011 | pmid = 21895796 | pmc = 3192301 | doi = 10.1111/j.1365-2958.2011.07827.x }}</ref><ref>{{cite journal | vauthors = Zawilak-Pawlik A, Kois A, Majka J, Jakimowicz D, Smulczyk-Krawczyszyn A, Messer W, Zakrzewska-Czerwińska J | title = Architecture of bacterial replication initiation complexes: orisomes from four unrelated bacteria | journal = The Biochemical Journal | volume = 389 | issue = Pt 2 | pages = 471–81 | date = July 2005 | pmid = 15790315 | pmc = 1175125 | doi = 10.1042/BJ20050143 }}</ref><ref name=":21">{{cite journal | vauthors = Grimwade JE, Rozgaja TA, Gupta R, Dyson K, Rao P, Leonard AC | title = Origin recognition is the predominant role for DnaA-ATP in initiation of chromosome replication | journal = Nucleic Acids Research | volume = 46 | issue = 12 | pages = 6140–6151 | date = July 2018 | pmid = 29800247 | pmc = 6158602 | doi = 10.1093/nar/gky457 }}</ref><ref>{{cite journal | vauthors = Sakiyama Y, Kasho K, Noguchi Y, Kawakami H, Katayama T | title = Regulatory dynamics in the ternary DnaA complex for initiation of chromosomal replication in Escherichia coli | journal = Nucleic Acids Research | volume = 45 | issue = 21 | pages = 12354–12373 | date = December 2017 | pmid = 29040689 | pmc = 5716108 | doi = 10.1093/nar/gkx914 }}</ref>

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 [[Adenosine triphosphate|ATP]]. 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.<ref name=":14" /><ref name="#2995681">{{cite journal | vauthors = Matsui M, Oka A, Takanami M, Yasuda S, Hirota Y | title = Sites of dnaA protein-binding in the replication origin of the Escherichia coli K-12 chromosome | journal = Journal of Molecular Biology | volume = 184 | issue = 3 | pages = 529–33 | date = August 1985 | pmid = 2995681 | doi = 10.1016/0022-2836(85)90299-2 }}</ref><ref name="#8663334">{{cite journal | vauthors = Margulies C, Kaguni JM | title = Ordered and sequential binding of DnaA protein to oriC, the chromosomal origin of Escherichia coli | journal = The Journal of Biological Chemistry | volume = 271 | issue = 29 | pages = 17035–40 | date = July 1996 | pmid = 8663334 | doi = 10.1074/jbc.271.29.17035 | doi-access = free }}</ref><ref name="#7615570">{{cite journal | vauthors = Schaper S, Messer W | title = Interaction of the initiator protein DnaA of Escherichia coli with its DNA target | journal = The Journal of Biological Chemistry | volume = 270 | issue = 29 | pages = 17622–6 | date = July 1995 | pmid = 7615570 | doi = 10.1074/jbc.270.29.17622 | doi-access = free }}</ref><ref name="#9351837">{{cite journal | vauthors = Weigel C, Schmidt A, Rückert B, Lurz R, Messer W | title = DnaA protein binding to individual DnaA boxes in the Escherichia coli replication origin, oriC | journal = The EMBO Journal | volume = 16 | issue = 21 | pages = 6574–83 | date = November 1997 | pmid = 9351837 | doi = 10.1093/emboj/16.21.6574 | pmc = 1170261 }}</ref><ref name="#2542031">{{cite journal | vauthors = Samitt CE, Hansen FG, Miller JF, Schaechter M | title = In vivo studies of DnaA binding to the origin of replication of Escherichia coli | journal = The EMBO Journal | volume = 8 | issue = 3 | pages = 989–93 | date = March 1989 | pmid = 2542031 | pmc = 400901 | doi = 10.1002/j.1460-2075.1989.tb03462.x }}</ref> 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.<ref name="#14978287">{{cite journal | vauthors = McGarry KC, Ryan VT, Grimwade JE, Leonard AC | title = Two discriminatory binding sites in the Escherichia coli replication origin are required for DNA strand opening by initiator DnaA-ATP | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 9 | pages = 2811–6 | date = March 2004 | pmid = 14978287 | pmc = 365702 | doi = 10.1073/pnas.0400340101 | bibcode = 2004PNAS..101.2811M | doi-access = free }}</ref><ref name="#15901724">{{cite journal | vauthors = Kawakami H, Keyamura K, Katayama T | title = Formation of an ATP-DnaA-specific initiation complex requires DnaA Arginine 285, a conserved motif in the AAA+ protein family | journal = The Journal of Biological Chemistry | volume = 280 | issue = 29 | pages = 27420–30 | date = July 2005 | pmid = 15901724 | doi = 10.1074/jbc.M502764200 | doi-access = free }}</ref><ref name="#10545126">{{cite journal | vauthors = Speck C, Weigel C, Messer W | title = ATP- and ADP-dnaA protein, a molecular switch in gene regulation | journal = The EMBO Journal | volume = 18 | issue = 21 | pages = 6169–76 | date = November 1999 | pmid = 10545126 | doi = 10.1093/emboj/18.21.6169 | pmc = 1171680 }}</ref><ref name=":21" /> 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.<ref name=":17" /><ref name="#19833870">{{cite journal | vauthors = Miller DT, Grimwade JE, Betteridge T, Rozgaja T, Torgue JJ, Leonard AC | title = Bacterial origin recognition complexes direct assembly of higher-order DnaA oligomeric structures | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 44 | pages = 18479–84 | date = November 2009 | pmid = 19833870 | pmc = 2773971 | doi = 10.1073/pnas.0909472106 | bibcode = 2009PNAS..10618479M | doi-access = free }}</ref><ref name="#16829961">{{cite journal | vauthors = Erzberger JP, Mott ML, Berger JM | title = Structural basis for ATP-dependent DnaA assembly and replication-origin remodeling | journal = Nature Structural & Molecular Biology | volume = 13 | issue = 8 | pages = 676–83 | date = August 2006 | pmid = 16829961 | doi = 10.1038/nsmb1115 | s2cid = 23586302 }}</ref><ref name="#22581769">{{cite journal | vauthors = Zorman S, Seitz H, Sclavi B, Strick TR | title = Topological characterization of the DnaA-oriC complex using single-molecule nanomanipuation | journal = Nucleic Acids Research | volume = 40 | issue = 15 | pages = 7375–83 | date = August 2012 | pmid = 22581769 | pmc = 3424547 | doi = 10.1093/nar/gks371 }}</ref> 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.<ref name="#27281207">{{cite journal | vauthors = Richardson TT, Harran O, Murray H | title = The bacterial DnaA-trio replication origin element specifies single-stranded DNA initiator binding | journal = Nature | volume = 534 | issue = 7607 | pages = 412–6 | date = June 2016 | pmid = 27281207 | pmc = 4913881 | doi = 10.1038/nature17962 | bibcode = 2016Natur.534..412R }}</ref> The engagement of single-stranded trinucleotide segments by the initiator filament stretches DNA and stabilizes the initiation bubble by preventing reannealing.<ref name=":19" /> The DnaA-trio origin element is conserved in many bacterial species, indicating it is a key element for origin function.<ref name="#27281207" /> 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.<ref name="Ekundayo et al"/>

Although the different DNA binding activities of DnaA have been extensively studied biochemically and various ''apo'', ssDNA-, or dsDNA-bound structures have been determined,<ref name=":18" /><ref name=":19" /><ref name=":20" /><ref name="#16829961" /> 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).<ref name="#16829961" /><ref name="#20595381">{{cite journal | vauthors = Duderstadt KE, Mott ML, Crisona NJ, Chuang K, Yang H, Berger JM | title = Origin remodeling and opening in bacteria rely on distinct assembly states of the DnaA initiator | journal = The Journal of Biological Chemistry | volume = 285 | issue = 36 | pages = 28229–39 | date = September 2010 | pmid = 20595381 | pmc = 2934688 | doi = 10.1074/jbc.M110.147975 | doi-access = free }}</ref> By contrast, in the loop-back model, the DNA is sharply bent in ''oriC'' and folds back onto the initiator filament so that DnaA [[Promoter (genetics)|protomer]]s simultaneously engage double- and single-stranded DNA regions.<ref name="#22053082">{{cite journal | vauthors = Ozaki S, Katayama T | title = Highly organized DnaA-oriC complexes recruit the single-stranded DNA for replication initiation | journal = Nucleic Acids Research | volume = 40 | issue = 4 | pages = 1648–65 | date = February 2012 | pmid = 22053082 | pmc = 3287180 | doi = 10.1093/nar/gkr832 }}</ref> 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.<ref name="Ekundayo et al"/>