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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2004 Jan 29;359(1441):39–47. doi: 10.1098/rstb.2003.1363

Disentangling DNA during replication: a tale of two strands.

Christine D Hardy 1, Nancy J Crisona 1, Michael D Stone 1, Nicholas R Cozzarelli 1
PMCID: PMC1693293  PMID: 15065655

Abstract

The seminal papers by Watson and Crick in 1953 on the structure and function of DNA clearly enunciated the challenge their model presented of how the intertwined strands of DNA are unwound and separated for replication to occur. We first give a historical overview of the major discoveries in the past 50 years that address this challenge. We then describe in more detail the cellular mechanisms responsible for the unlinking of DNA. No single strategy on its own accounts for the complete unlinking of chromosomes required for DNA segregation to proceed. Rather, it is the combined effects of topoisomerase action, chromosome organization and DNA-condensing proteins that allow the successful partitioning of chromosomes into dividing cells. Finally, we propose a model of chromosome structure, consistent with recent findings, that explains how the problem of unlinking is alleviated by the division of chromosomal DNA into manageably sized domains.

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Selected References

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  1. Adams D. E., Shekhtman E. M., Zechiedrich E. L., Schmid M. B., Cozzarelli N. R. The role of topoisomerase IV in partitioning bacterial replicons and the structure of catenated intermediates in DNA replication. Cell. 1992 Oct 16;71(2):277–288. doi: 10.1016/0092-8674(92)90356-h. [DOI] [PubMed] [Google Scholar]
  2. Bliska J. B., Cozzarelli N. R. Use of site-specific recombination as a probe of DNA structure and metabolism in vivo. J Mol Biol. 1987 Mar 20;194(2):205–218. doi: 10.1016/0022-2836(87)90369-x. [DOI] [PubMed] [Google Scholar]
  3. Brown P. O., Cozzarelli N. R. A sign inversion mechanism for enzymatic supercoiling of DNA. Science. 1979 Nov 30;206(4422):1081–1083. doi: 10.1126/science.227059. [DOI] [PubMed] [Google Scholar]
  4. CAIRNS J. The bacterial chromosome and its manner of replication as seen by autoradiography. J Mol Biol. 1963 Mar;6:208–213. doi: 10.1016/s0022-2836(63)80070-4. [DOI] [PubMed] [Google Scholar]
  5. Champoux J. J., Dulbecco R. An activity from mammalian cells that untwists superhelical DNA--a possible swivel for DNA replication (polyoma-ethidium bromide-mouse-embryo cells-dye binding assay). Proc Natl Acad Sci U S A. 1972 Jan;69(1):143–146. doi: 10.1073/pnas.69.1.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cobbe N., Heck M. M. Review: SMCs in the world of chromosome biology- from prokaryotes to higher eukaryotes. J Struct Biol. 2000 Apr;129(2-3):123–143. doi: 10.1006/jsbi.2000.4255. [DOI] [PubMed] [Google Scholar]
  7. Gellert M., Mizuuchi K., O'Dea M. H., Nash H. A. DNA gyrase: an enzyme that introduces superhelical turns into DNA. Proc Natl Acad Sci U S A. 1976 Nov;73(11):3872–3876. doi: 10.1073/pnas.73.11.3872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hagstrom Kirsten A., Holmes Victor F., Cozzarelli Nicholas R., Meyer Barbara J. C. elegans condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis. Genes Dev. 2002 Mar 15;16(6):729–742. doi: 10.1101/gad.968302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hiraga S., Niki H., Imamura R., Ogura T., Yamanaka K., Feng J., Ezaki B., Jaffé A. Mutants defective in chromosome partitioning in E. coli. Res Microbiol. 1991 Feb-Apr;142(2-3):189–194. doi: 10.1016/0923-2508(91)90029-a. [DOI] [PubMed] [Google Scholar]
  10. Hirano T., Mitchison T. J. A heterodimeric coiled-coil protein required for mitotic chromosome condensation in vitro. Cell. 1994 Nov 4;79(3):449–458. doi: 10.1016/0092-8674(94)90254-2. [DOI] [PubMed] [Google Scholar]
  11. Hirano Tatsuya. The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair. Genes Dev. 2002 Feb 15;16(4):399–414. doi: 10.1101/gad.955102. [DOI] [PubMed] [Google Scholar]
  12. Holmes V. F., Cozzarelli N. R. Closing the ring: links between SMC proteins and chromosome partitioning, condensation, and supercoiling. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1322–1324. doi: 10.1073/pnas.040576797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hooper D. C. Bacterial topoisomerases, anti-topoisomerases, and anti-topoisomerase resistance. Clin Infect Dis. 1998 Aug;27 (Suppl 1):S54–S63. doi: 10.1086/514923. [DOI] [PubMed] [Google Scholar]
  14. Kato J., Nishimura Y., Suzuki H. Escherichia coli parA is an allele of the gyrB gene. Mol Gen Genet. 1989 May;217(1):178–181. doi: 10.1007/BF00330959. [DOI] [PubMed] [Google Scholar]
  15. Kido M., Yamanaka K., Mitani T., Niki H., Ogura T., Hiraga S. RNase E polypeptides lacking a carboxyl-terminal half suppress a mukB mutation in Escherichia coli. J Bacteriol. 1996 Jul;178(13):3917–3925. doi: 10.1128/jb.178.13.3917-3925.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kimura K., Hirano T. ATP-dependent positive supercoiling of DNA by 13S condensin: a biochemical implication for chromosome condensation. Cell. 1997 Aug 22;90(4):625–634. doi: 10.1016/s0092-8674(00)80524-3. [DOI] [PubMed] [Google Scholar]
  17. Kimura K., Rybenkov V. V., Crisona N. J., Hirano T., Cozzarelli N. R. 13S condensin actively reconfigures DNA by introducing global positive writhe: implications for chromosome condensation. Cell. 1999 Jul 23;98(2):239–248. doi: 10.1016/s0092-8674(00)81018-1. [DOI] [PubMed] [Google Scholar]
  18. Kreuzer K. N., Cozzarelli N. R. Formation and resolution of DNA catenanes by DNA gyrase. Cell. 1980 May;20(1):245–254. doi: 10.1016/0092-8674(80)90252-4. [DOI] [PubMed] [Google Scholar]
  19. LEVI H. Improved alpha-track autoradiographs of biological specimens. Nature. 1953 Jan 17;171(4342):123–124. doi: 10.1038/171123a0. [DOI] [PubMed] [Google Scholar]
  20. Lindow Janet C., Britton Robert A., Grossman Alan D. Structural maintenance of chromosomes protein of Bacillus subtilis affects supercoiling in vivo. J Bacteriol. 2002 Oct;184(19):5317–5322. doi: 10.1128/JB.184.19.5317-5322.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Losada A., Hirano T. Shaping the metaphase chromosome: coordination of cohesion and condensation. Bioessays. 2001 Oct;23(10):924–935. doi: 10.1002/bies.1133. [DOI] [PubMed] [Google Scholar]
  22. Meyer B. J. Sex in the wormcounting and compensating X-chromosome dose. Trends Genet. 2000 Jun;16(6):247–253. doi: 10.1016/s0168-9525(00)02004-7. [DOI] [PubMed] [Google Scholar]
  23. Nasmyth Kim. Segregating sister genomes: the molecular biology of chromosome separation. Science. 2002 Jul 26;297(5581):559–565. doi: 10.1126/science.1074757. [DOI] [PubMed] [Google Scholar]
  24. Niki H., Jaffé A., Imamura R., Ogura T., Hiraga S. The new gene mukB codes for a 177 kd protein with coiled-coil domains involved in chromosome partitioning of E. coli. EMBO J. 1991 Jan;10(1):183–193. doi: 10.1002/j.1460-2075.1991.tb07935.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nitiss John L. DNA topoisomerases in cancer chemotherapy: using enzymes to generate selective DNA damage. Curr Opin Investig Drugs. 2002 Oct;3(10):1512–1516. [PubMed] [Google Scholar]
  26. Ohsumi K., Yamazoe M., Hiraga S. Different localization of SeqA-bound nascent DNA clusters and MukF-MukE-MukB complex in Escherichia coli cells. Mol Microbiol. 2001 May;40(4):835–845. doi: 10.1046/j.1365-2958.2001.02447.x. [DOI] [PubMed] [Google Scholar]
  27. Pohl W. F., Roberts G. W. Topological considerations in the theory of replication of DNA. J Math Biol. 1978 Oct 25;6(4):383–402. doi: 10.1007/BF02463003. [DOI] [PubMed] [Google Scholar]
  28. Postow L., Crisona N. J., Peter B. J., Hardy C. D., Cozzarelli N. R. Topological challenges to DNA replication: conformations at the fork. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8219–8226. doi: 10.1073/pnas.111006998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rybenkov V. V., Ullsperger C., Vologodskii A. V., Cozzarelli N. R. Simplification of DNA topology below equilibrium values by type II topoisomerases. Science. 1997 Aug 1;277(5326):690–693. doi: 10.1126/science.277.5326.690. [DOI] [PubMed] [Google Scholar]
  30. Rybenkov V. V., Vologodskii A. V., Cozzarelli N. R. The effect of ionic conditions on the conformations of supercoiled DNA. II. Equilibrium catenation. J Mol Biol. 1997 Mar 28;267(2):312–323. doi: 10.1006/jmbi.1996.0877. [DOI] [PubMed] [Google Scholar]
  31. Saitoh N., Goldberg I., Earnshaw W. C. The SMC proteins and the coming of age of the chromosome scaffold hypothesis. Bioessays. 1995 Sep;17(9):759–766. doi: 10.1002/bies.950170905. [DOI] [PubMed] [Google Scholar]
  32. Sawitzke J. A., Austin S. Suppression of chromosome segregation defects of Escherichia coli muk mutants by mutations in topoisomerase I. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1671–1676. doi: 10.1073/pnas.030528397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sawitzke J., Austin S. An analysis of the factory model for chromosome replication and segregation in bacteria. Mol Microbiol. 2001 May;40(4):786–794. doi: 10.1046/j.1365-2958.2001.02350.x. [DOI] [PubMed] [Google Scholar]
  34. Schmid M. B. A locus affecting nucleoid segregation in Salmonella typhimurium. J Bacteriol. 1990 Sep;172(9):5416–5424. doi: 10.1128/jb.172.9.5416-5424.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Strunnikov A. V., Hogan E., Koshland D. SMC2, a Saccharomyces cerevisiae gene essential for chromosome segregation and condensation, defines a subgroup within the SMC family. Genes Dev. 1995 Mar 1;9(5):587–599. doi: 10.1101/gad.9.5.587. [DOI] [PubMed] [Google Scholar]
  36. Sundin O., Varshavsky A. Arrest of segregation leads to accumulation of highly intertwined catenated dimers: dissection of the final stages of SV40 DNA replication. Cell. 1981 Sep;25(3):659–669. doi: 10.1016/0092-8674(81)90173-2. [DOI] [PubMed] [Google Scholar]
  37. Sutani T., Yanagida M. DNA renaturation activity of the SMC complex implicated in chromosome condensation. Nature. 1997 Aug 21;388(6644):798–801. doi: 10.1038/42062. [DOI] [PubMed] [Google Scholar]
  38. WATSON J. D., CRICK F. H. Genetical implications of the structure of deoxyribonucleic acid. Nature. 1953 May 30;171(4361):964–967. doi: 10.1038/171964b0. [DOI] [PubMed] [Google Scholar]
  39. Wang J. C. Interaction between DNA and an Escherichia coli protein omega. J Mol Biol. 1971 Feb 14;55(3):523–533. doi: 10.1016/0022-2836(71)90334-2. [DOI] [PubMed] [Google Scholar]
  40. Weitao T., Nordström K., Dasgupta S. Mutual suppression of mukB and seqA phenotypes might arise from their opposing influences on the Escherichia coli nucleoid structure. Mol Microbiol. 1999 Oct;34(1):157–168. doi: 10.1046/j.1365-2958.1999.01589.x. [DOI] [PubMed] [Google Scholar]
  41. Worcel A., Burgi E. On the structure of the folded chromosome of Escherichia coli. J Mol Biol. 1972 Nov 14;71(2):127–147. doi: 10.1016/0022-2836(72)90342-7. [DOI] [PubMed] [Google Scholar]
  42. Yamanaka K., Ogura T., Niki H., Hiraga S. Identification of two new genes, mukE and mukF, involved in chromosome partitioning in Escherichia coli. Mol Gen Genet. 1996 Feb 25;250(3):241–251. doi: 10.1007/BF02174381. [DOI] [PubMed] [Google Scholar]
  43. Zechiedrich E. L., Cozzarelli N. R. Roles of topoisomerase IV and DNA gyrase in DNA unlinking during replication in Escherichia coli. Genes Dev. 1995 Nov 15;9(22):2859–2869. doi: 10.1101/gad.9.22.2859. [DOI] [PubMed] [Google Scholar]
  44. Zechiedrich E. L., Khodursky A. B., Cozzarelli N. R. Topoisomerase IV, not gyrase, decatenates products of site-specific recombination in Escherichia coli. Genes Dev. 1997 Oct 1;11(19):2580–2592. doi: 10.1101/gad.11.19.2580. [DOI] [PMC free article] [PubMed] [Google Scholar]

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