Cell Biochemistry and Biophysics

, Volume 35, Issue 3, pp 289–301 | Cite as

Replication-related activities establish cohesion between sister chromatids

Orginal Article


Replicated sister chromatids are held together from their synthesis in S phase to their separation in anaphase. The process of sister chromatid cohesion is essential for the proper segregation of chromosomes in eukaroytic cells. Recent studies in Saccharomyces cerevisiae have advanced our understanding of how sister chromatid cohesion is established, maintained, and dissolved during the cell cycle. Historical observations have suggested that establishment of cohesion is roughly coincident with replication fork passage. Emerging evidence now indicates that replication fork components, such as PCNA, a novel DNA polymerase, Trf4p/Pol σ (formerly Trf4p/Pol κ), and a modified clamp-loader complex, actively participate in the process of the cohesion establishment. Here, we review the molecular events in the chromosome cycle with respect to cohesion. Failure of sister chromatid cohesion results in the aneuploidy characteristic of many birth defects and tumors in humans.

Index Entries

DNA replication cohension DNA polymerase SMC 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Guacci, V., Hogan, E., and Koshland, D. (1994) Chromosome condensation and sister chromatid pairing in budding yeas. J. Cell. Biol. 125, 517–530.PubMedCrossRefGoogle Scholar
  2. 2.
    Selig, S., Okumura, K., Ward, D. C., and Cedar, H. (1992) Delineation of DNA replication time zones by fluorescence in situ hybridization. EMBO J. 11, 1217–1225.PubMedGoogle Scholar
  3. 3.
    Sumner, A. T. (1991) Scanning electron microscopy of mammalian chromosomes from prophase to telophase. Chromosoma 100, 410–418.PubMedCrossRefGoogle Scholar
  4. 4.
    Rieder, C. L. (1982) The formation, structure, and composition of the mammalian kinetochore and kinetochore fiber. Int. Rev. Cytol. 79, 1–58.PubMedCrossRefGoogle Scholar
  5. 5.
    Tanaka, K., Yonekawa, T., Kawasaki, Y., Kai, M., Furuya, K., Iwasaki, M., et al. (2000) Fission yeast eso1p is required for establishing sister chromatid cohesion during S phase. Mol. Cell. Biol. 20, 3459–3469.PubMedCrossRefGoogle Scholar
  6. 6.
    McNeill, P. A. and Berns, M. W. (1981) Chromosome behavior after laser microirradiation of a single kinetochore in mitotic PtK2 cells. J. Cell. Biol. 88, 543–553.PubMedCrossRefGoogle Scholar
  7. 7.
    Rieder, C. L., Davison, E. A., Jensen, L. C., Cassimeris, L., and Salmon, E. D. (1986) Oscillatory movements of monooriented chromosomes and their position relative to the spindle pole result from the ejection properties of the aster and half-spindle. J. Cell. Biol. 103, 581–591.PubMedCrossRefGoogle Scholar
  8. 8.
    Skibbens, R. V., Rieder, C. L., and Salmon, E. D. (1995) Kinetochore motility after severing between sister centromeres using laser microsurgery: evidence that kinetochore directional instability and position is regulated by tension. J. Cell. Sci. 108, 2537–2548.PubMedGoogle Scholar
  9. 9.
    Boy de la Tour, E. and Laemmli, U. K. (1988) The metaphase scaffold is helically folded: sister chromatids have predominantly opposite helical handedness. Cell 55 937–944.PubMedCrossRefGoogle Scholar
  10. 10.
    Guacci, V., Koshland, D. and Strunnikov, A. (1997) A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae [see comments]. Cell 91, 47–57.PubMedCrossRefGoogle Scholar
  11. 11.
    Rieder, C. L., Cole, R. W., Khodjakov, A., and Sluder, G. (1995) The checkpoint delaying anaphase in response to chromosome monoori-entation is mediated by an inhibitory signal produced by unattached kinetochores. J. Cell. Biol. 130, 941–948.PubMedCrossRefGoogle Scholar
  12. 12.
    Hoyt, M. A., Trotis, L., and Roberts, B. T. (1991) S. cerevisiae genes required for cell cycle arrest in response to loss of microtuble function. Cell 66, 507–517.PubMedCrossRefGoogle Scholar
  13. 13.
    Li, R. and Murray, A. W. (1991) Feedback control of mitosis in budding yeast. Cell 66, 519–531.PubMedCrossRefGoogle Scholar
  14. 14.
    Cohen-Fix, O., Peters, J. M., Kirschner, M. W., and Koshland, D. (1996) Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent, degradation of the anaphase inhibitor Pds1p. Genes Dev. 10, 3081–3093.PubMedCrossRefGoogle Scholar
  15. 15.
    Nicklas, R. B., Ward, S. C., and Gorbsky, G. J. (1995) Kinetochore chemistry is sensitive to tension and may link mitotic forces to a cell cycle checkpoint. J. Cell. Biol. 130, 929–939.PubMedCrossRefGoogle Scholar
  16. 16.
    Gardner, R. D. and Burke, D. J. (2000) The spindle chekpoint: two transitions, two pathways. Trends Cell Biol. 10, 154–158.PubMedCrossRefGoogle Scholar
  17. 17.
    Hirano, T. and Mitchison, T.J. (1994) A heterodimeric coiled-coil protein required for mitotic chromosome condensation in vitro. Cell 79, 449–458.PubMedCrossRefGoogle Scholar
  18. 18.
    Koshland, D. E. and Guacci, V. (2000) Sister chromatid cohesion: the beginning of a long and beautiful relationship. Curr. Opin. Cell. Biol. 12, 297–301.PubMedCrossRefGoogle Scholar
  19. 19.
    Nasmyth, K., Peters, J. M., and Uhlmann, F. (2000) Splitting the chromosome: cutting the ties that bind sister chromatids. Science 288, 1379–1385.PubMedCrossRefGoogle Scholar
  20. 20.
    Cozzarelli, N. R. and Wang, J. C. (1990) DNA topology and its biological effects.Google Scholar
  21. 21.
    DiNardo, S., Voelkel, K., and Sternglanz, R. (1984) DNA topoisomerase II mutant of Saccharomyces cerevisiae: topoisomerase II is required for segregation of daughter molecules at the termination of DNA replication. Proc. Natl. Acad. Sci. USA 81, 2616–2620.PubMedCrossRefGoogle Scholar
  22. 22.
    Holm, C., Goto, T., Wang, J. C., and Botstein, D. (1985) DNA topoisomerase II is required at the time of mitosis in yeast. Cell 41, 553–563.PubMedCrossRefGoogle Scholar
  23. 23.
    Koshland, D. and Hartwell, L. H. (1987) The structure of sister minichromosome DNA before anaphase in Saccharomyces cerevisiae. Science 238, 1713–1716.PubMedCrossRefGoogle Scholar
  24. 24.
    Downes, C. S., Mullinger, A. M., and Johnson, R. T. (1991) Inhibitors of DNA topoisomerase II prevent chromatid separation in mammalian cells but do not prevent exit from mitosis. Proc. Natl. Acad. Sci. USA 88, 8895–8899.PubMedCrossRefGoogle Scholar
  25. 25.
    Holloway, S. L., Glotzer, M., King, R. W., and Murray, A. W. (1993) Anaphase is initiated by proteolysis rather than by the inactivation of maturation-promoting factor. Cell 73, 1393–1402.PubMedCrossRefGoogle Scholar
  26. 26.
    Surana, U., Amon, A., Dowzer, C., McGrew, J., Byers, B., and Nasmyth, K. (1993) Destruction of the CDC28/CLB mitotic kinase is not required for the metaphase to anaphase transition in budding yeast. EMBO J. 12, 1969–1978.PubMedGoogle Scholar
  27. 27.
    Irniger, S., Piatti, S., Michaelis, C., and Nasmyth, K. (1995) Genes involved in sister chromatid separation are needed for B-type cyclin proteolysis in budding yeast. Cell 81, 269–278. erratum: Cell 93(3), 487 (1998).PubMedCrossRefGoogle Scholar
  28. 28.
    King, R. W., Peters, J. M., Tugendreich, S., Rolfe, M., Hieter, P., and Kirschner, M. W. (1995) A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin tocyclin B. Cell 81, 279–288.PubMedCrossRefGoogle Scholar
  29. 29.
    Straight, A. F., Belmont, A. S., Robinett, C. C., and Murray, A. W. (1996) GFP tagging of budding yeast chromosomes reveals that protein-protein interactions can mediate sister chromatid cohesion. Curr. Biol. 6, 1599–1608.PubMedCrossRefGoogle Scholar
  30. 30.
    Yamamoto, A., Guacci, V., and Koshland, D. (1996) Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae. J. Cell. Biol. 133, 85–97.PubMedCrossRefGoogle Scholar
  31. 31.
    Funabiki, H., Kumada, K., and Yanagida, M. (1996) Fission yeast Cut1 and Cut2 are essential for sister chromatid separation, concentrate along the metaphase spindle and form large complexes. EMBO J. 15, 6617–6628.PubMedGoogle Scholar
  32. 32.
    Funabiki, H., Yamano, H., Nagao, K., Tanaka, H., Yasuda, H., Hunt, T., et al. (1997) Fission yeast Cut2 required for anaphase has two destruction boxes. EMBO J. 16, 5977–5987.PubMedCrossRefGoogle Scholar
  33. 33.
    Ciosk, R., Zachariae, W., Michaelis, C., Shevchenko, A., Mann, M., and Nasmyth, K. (1998) An Esp1/Pds1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 93, 1067–1076.PubMedCrossRefGoogle Scholar
  34. 34.
    Hwang, L. H., Lau, L. F., Smith, D. L., Mistrot, C. A., Hardwick, K. G., Hwang, E. S., et al. (1998) Budding yeast Cdc20: a target of the spindle checkpoint [see comments]. Science 279, 1041–1044.PubMedCrossRefGoogle Scholar
  35. 35.
    Michaelis, C., Ciosk, R., and Nasmyth, K. (1997) Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell 91, 35–45.PubMedCrossRefGoogle Scholar
  36. 36.
    Strunnikov, A. V., Hogan, E., and Koshland, D. (1995) SMC2, a Saccharomyces cerevisiae gene essential for chromosome segregation and condensation, defines a subgroup within the SMC family. Genes Dev. 9, 587–599.PubMedCrossRefGoogle Scholar
  37. 37.
    Hirano, T. (2000) Chromosome cohesion, condensation separation. Annu. Rev. Biochem. 69, 115–144.PubMedCrossRefGoogle Scholar
  38. 38.
    Losada, A., Hirano, M., and Hirano, T. (1998) Identification of Xenopus SMC protein complexes required for sister chromatid cohesion. Genes Dev 12, 1986–1997.PubMedGoogle Scholar
  39. 39.
    Tomonaga, T., Nagao, K., Kawasaki, Y., Furuya, K., Murakami, A., Morishita, J., et al. (2000) Characterization of fission yeast cohesin: essential anaphase proteolysis of rad21 phosphorylated in the S phase. Genes Dev. 14, 2757–2770.PubMedCrossRefGoogle Scholar
  40. 40.
    Toth, A., Ciosk, R., Uhlmann, F., Galova, M., Schleiffer, A., and Nasmyth, K. (1999) Yeast Cohesin complex requires a conserved protein, Eco1p(Ctf7), to establish cohension between sister chromatids during DNA replication. Genes Dev. 13, 320–333.PubMedGoogle Scholar
  41. 41.
    Losada, A., Yokochi, T., Kobayashi, R., and Hirano, T. (2000) Identification and characterization of SA/Scc3p subunits in the Xenopus and human cohesin complexes. J. Cell. Biol. 150, 405–416.PubMedCrossRefGoogle Scholar
  42. 42.
    Sumara, I., Vorlaufer, E., Gieffers, C., Peters, B. H., and Peters, J. M. (2000) Characterization of vertebrate cohesin complexes and their regulation in prophase. J. Cell. Biol. 151, 749–762.PubMedCrossRefGoogle Scholar
  43. 43.
    Waizenegger, I. C., Hauf, S., Meinke, A., and Peters, J. M. (2000) Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell 103, 399–410.PubMedCrossRefGoogle Scholar
  44. 44.
    Jessberger, R., Frei, C., and Gasser, S. M. (1998) Chromosome dynamics—the Smc protein family. Curr. Opin. Genet. Dev. 8, 254–259.PubMedCrossRefGoogle Scholar
  45. 45.
    melby, T. E., Ciampaglio, C. N., Briscoe, G., and Erickson, H. P. (1998) The symmetrical structure of structural maintenance of chromosomes (SMC) and MukB proteins: long, antiparallel coiled coils, folded at a flexible hinge. J. Cell. Biol. 142, 1595–1604.PubMedCrossRefGoogle Scholar
  46. 46.
    Hopfner, K. P., Karcher, A., Shin, D. S., Craig, L., Arthur, L. M., Carney, J. P., et al. (2000) Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101, 789–800.PubMedCrossRefGoogle Scholar
  47. 47.
    Akhmedov, A. T., Frei, C., Tsai-Pflugfelder, M., Kemper, B., Gasser, S. M., and Jessberger, R. (1998) Structural maintenance of chromosomes protein C-terminal domains bind preferentially to DNA with secondary structure. J. Biol. Chem. 273, 24,088–24,094.CrossRefGoogle Scholar
  48. 48.
    Losada, A. and Hirano, T. (2001) Intermolecular DNA interactions stimulated by the cohesin complex in vitro. Implications for sister chromatid cohesion. Curr. Biol. 11, 268–272.PubMedCrossRefGoogle Scholar
  49. 49.
    Uhlmann, F., Lottspeich, F., and Nasmyth, K. (1999) Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1 [see comments] Nature 400, 37–42.PubMedCrossRefGoogle Scholar
  50. 50.
    Uhlmann, F., Wernic, D., Poupart, M. A., Koonin, E. V., and Nasmyth, K. (2000) Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast. Cell 103, 375–386.PubMedCrossRefGoogle Scholar
  51. 51.
    Hartman, T., Stead, K., Koshland, D., and Guacci, V. (2000) Pds5p is an essential chromosomal protein required for both sister chromatid cohesion and condensation in Saccharomyces cerevisiae. J. Cell. Biol. 151, 613–626.PubMedCrossRefGoogle Scholar
  52. 52.
    van Heemst, D., James, F., Poggeler, S., Berteaux-Lecellier, V., and Zickler, D. (1999) Spo76p is a conserved chromosome morphogenesis protein that links the mitotic and meitotic programs. Cell 98, 261–271.PubMedCrossRefGoogle Scholar
  53. 53.
    Denison, S. H., Kafer, E., and May, G. S. (1993) Mutation in the bimD gene of Aspergillus nidulans confers a conditional mitotic block and sensitivity to DNA damaging agents. Genetics 134, 1085–1096.PubMedGoogle Scholar
  54. 54.
    Megee, P. C., Mistrot, C., Guacci, V., and Koshland, D. (1999) The centromeric sister chromatid cohesion site directs Mcd1p binding to adjacent sequences. Mol. Cell 4, 445–50.PubMedCrossRefGoogle Scholar
  55. 55.
    Blat, Y. and Kleckner, N. (1999) Cohesins bind to preferential sites along yeast chromosome III, with differential regulation along arms versus the centric region, Cell 98, 249–259.PubMedCrossRefGoogle Scholar
  56. 56.
    Laloraya, S., Guacci, V., and Koshland, D. (2000) Chromosomal addresses of the cohesin component Mcd1p. J. Cell. Biol. 151, 1047–1056.PubMedCrossRefGoogle Scholar
  57. 57.
    Tanaka, T., Cosma, M. P., Wirth, K., and Nasmyth, K. (1999) Identification of cohesin association sites at centromeres and along chromsome arms. Cell 98, 847–858.PubMedCrossRefGoogle Scholar
  58. 58.
    Ciosk, R., Shirayama, M., Shevchenko, A., Tanaka, T., Toth, A., Shevchenko, A., et al. (2000) Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. Mol. Cell 5, 243–254.PubMedCrossRefGoogle Scholar
  59. 59.
    Jones, S. and Sgouros, J. (2001) The cohesin complex: sequence homologies, interaction networks and shared motifs. Genome Biol. 2.Google Scholar
  60. 60.
    Uhlmann, F. and Nasmyth, K. (1998) Cohesion between sister chromatids must be established during DNA replication. Curr. Biol. 8, 1095–1101.PubMedCrossRefGoogle Scholar
  61. 61.
    Skibbens, R. V., Corson, L. B., Koshland, D., and Hieter, P. (1999) Ctf7p is essential for sister chromatid cohesion and links mitotic chromosome structure to the DNA replication machinery. Genes Dev. 13, 307–319.PubMedGoogle Scholar
  62. 62.
    Waga, S. and Stillman, B. (1998) The DNA replication fork in eukaryotic cells. Annu. Rev. Biochem. 67, 721–751.PubMedCrossRefGoogle Scholar
  63. 63.
    Skibbens, R. V. (2000) Holding your own: establishing sister chromatid cohesion. Genome Res. 10, 1664–1671.PubMedCrossRefGoogle Scholar
  64. 64.
    Wang, Z., Castano, I. B., De Las Penas, A., Adams, C., and Christman, M. F. (2000) Polkappa: a DNA polymerase required for sister chromatid cohesion. Science 289, 774–779.PubMedCrossRefGoogle Scholar
  65. 65.
    Tanaka, T., Fuchs, J., Loidl, J., and Nasmyth, K. (2000) Cohesin ensures bipolar attachment of microtubules to sister centromeres and resists their precocious separation. Nat. Cell. Biol. 2, 492–499.PubMedCrossRefGoogle Scholar
  66. 66.
    Castaño, I. B., Brzoska, P. M., Sadoff, B. U., Chen, H. Y., and Christman, M. F. (1996B) Mitotic chromosome condensation in the rDNA requires TRF4 and DNA topoisomerase I in Saccharomyces cerevisiae. Genes Dev. 10, 2564–2576.PubMedCrossRefGoogle Scholar
  67. 67.
    Castaão, I. B., Heath-Pagliuso, S., Sadoff, B. U., Fitzhugh, D. J., and Christman, M. F. (1996A) A novel family of TRF (DNA Topoisomerase I-Related Function) genes required for proper nuclear segregation. Nuclear Acids Res. 24, 2404–2410.CrossRefGoogle Scholar
  68. 68.
    Sadoff, B. U., Heath-Pagliuso, S., Castaño, I. B., Yingfang, Z., Kieff, F. S., and Christman, M. F., (1995) Isolation of Mutants of Saccharomyces cerevisiae requiring DNA topoisomerase I. Genetics 141, 465–479.PubMedGoogle Scholar
  69. 69.
    Walowsky, C., Fitzhugh, D. J., Castano, I. B., Ju, J. Y., Levin, N. A., and Christman, M. F. (1999) The topoisomerase-related function gene TRF4 affects cellular sensitivity to the antitumor agent camptothecin. J. Biol. Chem. 274, 7302–7308.PubMedCrossRefGoogle Scholar
  70. 70.
    Miller, A. M. and Nasmyth, K. A. (1984) Role of DNA replication in the repression of silent mating type loci in yeast. Nature 312, 247–251.PubMedCrossRefGoogle Scholar
  71. 71.
    Gerlach, V. L., Aravirid, L., Gotway, G., Schultz, R. A., Koonin, E. V., and Friedberg, E. C. (1999) Human and mouse homologs of Escherichia coli DinB (DNA polymerase IV), members of the UmuC/DinB superfamily. Proc. Natl. Acad. Sci. USA 96, 11,922–11,927.CrossRefGoogle Scholar
  72. 72.
    Johnson, R. E., Prakash, S., and Prakash, L. (1999) Efficient bypass of a thymine-thymine dimer by yeast DNA polymerase, Poleta. Sci. 283, 1001–1004.CrossRefGoogle Scholar
  73. 73.
    Tsurimoto, T. and Stillmman, B. (1991) Replication factors required for SV40 DNA replication in vitro. II. Switching of DNA polymerase alpha and delta during initiation of leading and lagging strand synthesis. J. Biol. Chem. 266, 1961–1968.PubMedGoogle Scholar
  74. 74.
    Waga, S. and Stillman, B. (1994) Anatomy of a DNA replication fork revealed by reconstitution of SV40 DNA replication in vitro. Nature 369, 207–212.PubMedCrossRefGoogle Scholar
  75. 75.
    Hanna, J. S., Kroll, E. S., Lundblad, V., and Spencer, F. A. (2001) Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion. Mol. Cell. Biol. 21, 3144–3158.PubMedCrossRefGoogle Scholar
  76. 76.
    Green, C. M., Erdjument-Bromage, H., Tempst, P., and Lowndes, N. F. (2000) A novel Rad24 checkpoint protein complex closely related to replication factor C. Curr. Biol. 10, 39–42; erratum Curr. Biol. 10(4), R171 (2000).PubMedCrossRefGoogle Scholar
  77. 77.
    Miles, J. and Formosa, T. (1992) Evidence that POB1, a Saccharomyces cerevisiae protein that binds to DNA polymerase alpha, acts in DNA metabolism in vivo. Mol. Cell. Biol. 12, 5724–5735.PubMedGoogle Scholar
  78. 78.
    Yamamoto, A., Guacci, V., and Koshland, D. (1996) Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s). J. Cell. Biol. 133, 99–110.PubMedCrossRefGoogle Scholar
  79. 79.
    Jensen, S., Segal, M., Clarke, D. J., and Reed, S. I. (2001) A novel role of the budding yeast separin Esp1 in anaphase spindle elongation: evidence that proper spindle association of Esp1 is regulated by Pds1. J. Cell. Biol. 152, 27–40.PubMedCrossRefGoogle Scholar
  80. 80.
    Zou, H., McGarry, T. J., Bernal, T., and Kirschner, M. W. (1999) Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis [see comments]. Science 285, 418–422.PubMedCrossRefGoogle Scholar
  81. 81.
    Lengauer, C., Kinzler, K. W., and Vogelstein, B. (1997) Genetic instability in colorectal cancers. Nature 386, 623–627.PubMedCrossRefGoogle Scholar
  82. 82.
    Cahill, D. P., Lengauer, C., Yu, J., Riggins, G. J., Willson, J. K., Markowitz, S. D., et al. (1998) Mutations of mitotic checkpoint genes in human cancers [see comments] Nature 392, 300–303.PubMedCrossRefGoogle Scholar
  83. 83.
    Weinert, T. A. (1992) Dual cell cycle checkpoints sensitive to chromosome replication and DNA damage in the budding yeast Saccharomyces cerevisiae. Radiat. Res. 132, 141–143.PubMedCrossRefGoogle Scholar
  84. 84.
    Canman, C. E., Lim, D. S., Cimprich, K. A., Taya, Y., Tamai, K., Sakaguchi, K., et al. (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677–1679.PubMedCrossRefGoogle Scholar
  85. 85.
    Ghiselli, G. and Iozzo, R. V. (2000) Over-expression of Bamacan/SMC3 causes transformation. J. Biol. Chem. 275, 20,235–20,238.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2001

Authors and Affiliations

  1. 1.Department of Genetics and Genomics, Evans Bldg.Boston University School of MedicineBoston

Personalised recommendations