Current Genetics

, Volume 63, Issue 4, pp 607–611 | Cite as

Control of bacterial chromosome replication by non-coding regions outside the origin

  • Jakob Frimodt-Møller
  • Godefroid Charbon
  • Anders Løbner-Olesen


Chromosome replication in Eubacteria is initiated by initiator protein(s) binding to specific sites within the replication origin, oriC. Recently, initiator protein binding to chromosomal regions outside the origin has attracted renewed attention; as such binding sites contribute to control the frequency of initiations. These outside-oriC binding sites function in several different ways: by steric hindrances of replication fork assembly, by titration of initiator proteins away from the origin, by performing a chaperone-like activity for inactivation- or activation of initiator proteins or by mediating crosstalk between chromosomes. Here, we discuss initiator binding to outside-oriC sites in a broad range of different taxonomic groups, to highlight the significance of such regions for regulation of bacterial chromosome replication. For Escherichia coli, it was recently shown that the genomic positions of regulatory elements are important for bacterial fitness, which, as we discuss, could be true for several other organisms.


Bacterial chromosomes Replication control Initiator protein Outside-oriC regions Genomic position 



The authors were funded by grants from the Novo Nordisk Foundation, the Lundbeck Foundation and from the Danish National Research Foundation (DNRF120) through the Center for Bacterial Stress Response and Persistence (BASP).


  1. Baek JH, Chattoraj DK (2014) Chromosome I controls chromosome II replication in Vibrio cholerae. PLoS Genet 10:e1004184. doi: 10.1371/journal.pgen.1004184 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Briggs GS, Smits WK, Soultanas P (2012) Chromosomal replication initiation machinery of low-G + C-content Firmicutes. J Bacteriol 194:5162–5170. doi: 10.1128/JB.00865-12 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Calcutt MJ, Schmidt FJ (1992) Conserved gene arrangement in the origin region of the Streptomyces coelicolor chromosome. J Bacteriol 174: 3220-3226 doi:Google Scholar
  4. Donczew R, Weigel C, Lurz R, Zakrzewska-Czerwinska J, Zawilak-Pawlik A (2012) Helicobacter pylori oriC–the first bipartite origin of chromosome replication in Gram-negative bacteria. Nucleic Acids Res 40:9647–9660. doi: 10.1093/nar/gks742 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Du WL, Dubarry N, Passot FM, Kamgoue A, Murray H, Lane D, Pasta F (2016) Orderly Replication and Segregation of the Four Replicons of Burkholderia cenocepacia J2315. PLoS Genet 12:e1006172. doi: 10.1371/journal.pgen.1006172 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Duigou S, Knudsen KG, Skovgaard O, Egan ES, Lobner-Olesen A, Waldor MK (2006) Independent control of replication initiation of the two Vibrio cholerae chromosomes by DnaA and RctB. J Bacteriol 188:6419–6424. doi: 10.1128/JB.00565-06 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Egan ES, Waldor MK (2003) Distinct replication requirements for the two Vibrio cholerae chromosomes. Cell 114: 521–530Google Scholar
  8. Frimodt-Moller J, Charbon G, Krogfelt KA, Lobner-Olesen A (2015) Control regions for chromosome replication are conserved with respect to sequence and location among Escherichia coli strains. Front Microbiol 6:1011 doi:  10.3389/fmicb.2015.01011
  9. Frimodt-Moller J, Charbon G, Krogfelt KA, Lobner-Olesen A (2016) DNA replication control is linked to genomic positioning of control regions in Escherichia coli. PLoS Genet 12:e1006286. doi: 10.1371/journal.pgen.1006286 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Fujimitsu K, Senriuchi T, Katayama T (2009) Specific genomic sequences of E. coli promote replicational initiation by directly reactivating ADP-DnaA. Genes Dev 23:1221–1233. doi: 10.1101/gad.1775809 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Fukuoka T, Moriya S, Yoshikawa H, Ogasawara N (1990) Purification and characterization of an initiation protein for chromosomal replication, DnaA, in Bacillus subtilis. J Biochem 107: 732–739Google Scholar
  12. Hansen FG, Koefoed S, Sorensen L, Atlung T (1987) Titration of DnaA protein by oriC DnaA-boxes increases dnaA gene expression in Escherichia coli. EMBO J 6:255–258PubMedPubMedCentralGoogle Scholar
  13. Harrison PW, Lower RP, Kim NK, Young JP (2010) Introducing the bacterial ‘chromid’: not a chromosome, not a plasmid. Trends Microbiol 18:141–148. doi: 10.1016/j.tim.2009.12.010 CrossRefPubMedGoogle Scholar
  14. Holden MT, Seth-Smith HM, Crossman LC, Sebaihia M, Bentley SD, Cerdeno-Tarraga AM, Thomson NR, Bason N, Quail MA, Sharp S, Cherevach I, Churcher C, Goodhead I, Hauser H, Holroyd N, Mungall K, Scott P, Walker D, White B, Rose H, Iversen P, Mil-Homens D, Rocha EP, Fialho AM, Baldwin A, Dowson C, Barrell BG, Govan JR, Vandamme P, Hart CA, Mahenthiralingam E, Parkhill J (2009) The genome of Burkholderia cenocepacia J2315, an epidemic pathogen of cystic fibrosis patients. J Bacteriol 191:261–277. doi: 10.1128/JB.01230-08 CrossRefPubMedGoogle Scholar
  15. Jha JK, Ramachandran R, Chattoraj DK (2016) Opening the strands of replication origins-still an open question. Front Mol Biosci 3:62. doi: 10.3389/fmolb.2016.00062 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kaguni JM (2011) Replication initiation at the Escherichia coli chromosomal origin. Curr Opin Chem Biol 15:606–613. doi: 10.1016/j.cbpa.2011.07.016 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kasho K, Katayama T (2013) DnaA binding locus datA promotes DnaA-ATP hydrolysis to enable cell cycle-coordinated replication initiation. Proc Natl Acad Sci U S A 110:936–941. doi: 10.1073/pnas.1212070110 CrossRefPubMedGoogle Scholar
  18. Kasho K, Fujimitsu K, Matoba T, Oshima T, Katayama T (2014) Timely binding of IHF and Fis to DARS2 regulates ATP-DnaA production and replication initiation. Nucleic Acids Res 42:13134–13149. doi: 10.1093/nar/gku1051 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Katayama T, Kubota T, Kurokawa K, Crooke E, Sekimizu K (1998) The initiator function of DnaA protein is negatively regulated by the sliding clamp of the E. coli chromosomal replicase. Cell 94:61–71CrossRefPubMedGoogle Scholar
  20. Kato J, Katayama T (2001) Hda, a novel DnaA-related protein, regulates the replication cycle in Escherichia coli. EMBO J 20:4253–4262. doi: 10.1093/emboj/20.15.4253 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kitagawa R, Mitsuki H, Okazaki T, Ogawa T (1996) A novel DnaA protein-binding site at 94.7 min on the Escherichia coli chromosome. Mol Microbiol 19:1137–1147CrossRefPubMedGoogle Scholar
  22. Kitagawa R, Ozaki T, Moriya S, Ogawa T (1998) Negative control of replication initiation by a novel chromosomal locus exhibiting exceptional affinity for Escherichia coli DnaA protein. Genes Dev 12:3032–3043CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kornberg A, Baker TA 1992 DNA Replication, Second Edition University Science BooksGoogle Scholar
  24. Kurokawa K, Nishida S, Emoto A, Sekimizu K, Katayama T (1999) Replication cycle-coordinated change of the adenine nucleotide-bound forms of DnaA protein in Escherichia coli. EMBO J 18:6642–6652. doi: 10.1093/emboj/18.23.6642 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Leimbach A, Hacker J, Dobrindt U (2013) E. coli as an all-rounder: the thin line between commensalism and pathogenicity. Curr Top Microbiol Immunol 358:3–32. doi: 10.1007/82_2012_303 PubMedGoogle Scholar
  26. Leonard AC, Grimwade JE (2011) Regulation of DnaA assembly and activity: taking directions from the genome. Annu Rev Microbiol 65:19–35. doi: 10.1146/annurev-micro-090110-102934 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lu M, Campbell JL, Boye E, Kleckner N (1994) SeqA: a negative modulator of replication initiation in E. coli. Cell 77:413–426CrossRefPubMedGoogle Scholar
  28. Mackiewicz P, Zakrzewska-Czerwinska J, Zawilak A, Dudek MR, Cebrat S (2004) Where does bacterial replication start? Rules for predicting the oriC region. Nucleic Acids Res 32:3781–3791. doi: 10.1093/nar/gkh699 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Majka J, Messer W, Schrempf H, Zakrzewska-Czerwinska J (1997) Purification and characterization of the Streptomyces lividans initiator protein DnaA. J Bacteriol 179:2426–2432CrossRefPubMedPubMedCentralGoogle Scholar
  30. Moriya S, Ogasawara N, Yoshikawa H (1985) Structure and function of the region of the replication origin of the Bacillus subtilis chromosome. III. Nucleotide sequence of some 10,000 base pairs in the origin region. Nucleic Acids Res 13:2251–2265CrossRefPubMedPubMedCentralGoogle Scholar
  31. Mott ML, Berger JM (2007) DNA replication initiation: mechanisms and regulation in bacteria. Nat Rev Microbiol 5:343–354. doi: 10.1038/nrmicro1640 CrossRefPubMedGoogle Scholar
  32. Natrajan G, Noirot-Gros MF, Zawilak-Pawlik A, Kapp U, Terradot L (2009) The structure of a DnaA/HobA complex from Helicobacter pylori provides insight into regulation of DNA replication in bacteria. Proc Natl Acad Sci USA 106:21115–21120. doi: 10.1073/pnas.0908966106 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Okumura H, Yoshimura M, Ueki M, Oshima T, Ogasawara N, Ishikawa S (2012) Regulation of chromosomal replication initiation by oriC-proximal DnaA-box clusters in Bacillus subtilis. Nucleic Acids Res 40:220–234. doi: 10.1093/nar/gkr716 CrossRefPubMedGoogle Scholar
  34. Ozaki S, Fujimitsu K, Kurumizaka H, Katayama T (2006) The DnaA homolog of the hyperthermophilic eubacterium Thermotoga maritima forms an open complex with a minimal 149-bp origin region in an ATP-dependent manner. Genes Cells 11:425–438. doi: 10.1111/j.1365-2443.2006.00950.x CrossRefPubMedGoogle Scholar
  35. Paulsson J, Chattoraj DK (2006) Origin inactivation in bacterial DNA replication control. Mol Microbiol 61:9–15. doi: 10.1111/j.1365-2958.2006.05229.x CrossRefPubMedGoogle Scholar
  36. Qin MH, Madiraju MV, Rajagopalan M (1999) Characterization of the functional replication origin of Mycobacterium tuberculosis. Gene 233:121–130CrossRefPubMedGoogle Scholar
  37. Riber L, Frimodt-Moller J, Charbon G, Lobner-Olesen A (2016) Multiple DNA binding proteins contribute to timing of chromosome replication in E. coli. Front Mol Biosci 3:29. doi: 10.3389/fmolb.2016.00029 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Roth A, Messer W (1998) High-affinity binding sites for the initiator protein DnaA on the chromosome of Escherichia coli. Mol Microbiol 28:395–401CrossRefPubMedGoogle Scholar
  39. Salazar L (2000) Inhibition of chromosome replication in Mycobacterium smegmatis: effect of the rpmH-dnaA promoter region. Microbiology 146(Pt 9):2199–2207. doi: 10.1099/00221287-146-9-2199 CrossRefPubMedGoogle Scholar
  40. Schaper S, Nardmann J, Luder G, Lurz R, Speck C, Messer W (2000) Identification of the chromosomal replication origin from Thermus thermophilus and its interaction with the replication initiator DnaA. J Mol Biol 299:655–665. doi: 10.1006/jmbi.2000.3764 CrossRefPubMedGoogle Scholar
  41. Sekimizu K, Bramhill D, Kornberg A (1987) ATP activates dnaA protein in initiating replication of plasmids bearing the origin of the E. coli chromosome. Cell 50:259–265CrossRefPubMedGoogle Scholar
  42. Smulczyk-Krawczyszyn A, Jakimowicz D, Ruban-Osmialowska B, Zawilak-Pawlik A, Majka J, Chater K, Zakrzewska-Czerwinska J (2006) Cluster of DnaA boxes involved in regulation of Streptomyces chromosome replication: from in silico to in vivo studies. J Bacteriol 188:6184–6194. doi: 10.1128/JB.00528-06 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Val ME, Marbouty M, de Lemos Martins F, Kennedy SP, Kemble H, Bland MJ, Possoz C, Koszul R, Skovgaard O, Mazel D (2016) A checkpoint control orchestrates the replication of the two chromosomes of Vibrio cholerae. Sci Adv 2:e1501914. doi: 10.1126/sciadv.1501914 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Venkova-Canova T, Chattoraj DK (2011) Transition from a plasmid to a chromosomal mode of replication entails additional regulators. Proc Natl Acad Sci USA 108:6199–6204. doi: 10.1073/pnas.1013244108 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Yamamoto K, Muniruzzaman S, Rajagopalan M, Madiraju MV (2002) Modulation of Mycobacterium tuberculosis DnaA protein-adenine-nucleotide interactions by acidic phospholipids. Biochem J 363:305–311PubMedPubMedCentralGoogle Scholar
  46. Zakrzewska-Czerwinska J, Jakimowicz D, Zawilak-Pawlik A, Messer W (2007) Regulation of the initiation of chromosomal replication in bacteria. FEMS Microbiol Rev 31:378–387. doi: 10.1111/j.1574-6976.2007.00070.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Biology, Section for Functional Genomics and Center for Bacterial Stress Response and Persistence (BASP)University of CopenhagenCopenhagenDenmark
  2. 2.Novo Nordisk Foundation Center for BiosustainabilityTechnical University of DenmarkLyngbyDenmark

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