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Replication structure of the human & beta;-globin gene domain

Nature volume 366, pages 588–590 (1993)Cite this article

Abstract

THE animal cell genome is organized into a series of replicons with an average size of 50–300 kilobases1; each of these units is characterized by its own origin of replication which serves as the point of initiation for DNA synthesis. In animal viruses, origin usage can be regulated by cis-acting elements2, and in some cases, replication may be cell-type specific3. Little is known, however, about the organization and control of endogenous tissue-specific gene replication. To understand this process, we have used a replication direction assay to examine DNA fragments covering more than 200 kilobases of the human & beta;-like globin domain, and have identified a single bidirectional origin located upstream of the β-globin itself. This locus is used to initiate DNA synthesis in expressing cells, where the globin domain replicates early, and in non-expressing cells, which are characterized by late replication of the same region4,5. Deletion of this origin sequence, as occurs in the haemoglobin Lepore syndrome6, cancels bidirectional DNA synthesis at this site and leads to a striking reversal of replication direction upstream to the locus. This represents the first genetic proof of the existence of specific, discrete origins of replication in animal cells.

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References

  1. Edenberg, H. J. & Huberman, J. A. A. Rev. Genet. 9, 245–284 (1975).

    Article  CAS  Google Scholar 

  2. DePamphilis, M. L. Cell 52, 635–638 (1988).

    Article  CAS  Google Scholar 

  3. de Villlers, J., Schaffner, W., Tyndall, C., Luplon, S. & Kamen, R. Nature 312, 242–246 (1984).

    Article  ADS  Google Scholar 

  4. Hatton, K. S. et al. Molec. cell. Biol. 8, 2149–2158 (1988).

    Article  CAS  Google Scholar 

  5. Epner, E., Forrester, W. C. & Groudine, M. Proc. natn. Acad. Sci. U.S.A. 85, 8081–8085 (1988).

    Article  ADS  CAS  Google Scholar 

  6. Flavell, R. A., Kooter, J. M., De Boer, E., Little, P. F. R. & Williamson, R. Cell 15, 25–41 (1978).

    Article  CAS  Google Scholar 

  7. Handeli, S., Klar, A., Meuth, M. & Cedar, H. Cell 57, 909–920 (1989).

    Article  CAS  Google Scholar 

  8. Anachkova, B. & Hamlin, J. L. Molec. cell. Biol. 9, 532–540 (1989).

    Article  CAS  Google Scholar 

  9. Vassilev, L. T., Burhans, W. C. & DePamphilis, M. L. Molec. cell. Biol. 10, 4685–4689 (1990).

    Article  CAS  Google Scholar 

  10. Burhans, W. C., Vassilev, L. T., Caddle, M. S., Heintz, N. H. & DePamphilis, M. L. Cell 62, 955–965 (1990).

    Article  CAS  Google Scholar 

  11. Vaughn, J. P., Dijkwel, P. A. & Hamlin, J. L. Cell 61, 1075–1087 (1990).

    Article  CAS  Google Scholar 

  12. Bergemann, A. D. & Johnson, E. M. Molec. cell. Biol. 12, 1257–1265 (1992).

    Article  CAS  Google Scholar 

  13. Selig, S., Okumura, K., Ward, D. C. & Cedar, H. EMBO J. 11, 1217–1225 (1992).

    Article  CAS  Google Scholar 

  14. Trempe, J. P., Lindstrom, Y. I. & Leffak, M. Molec. cell. Biol. 8, 1657–1663 (1988).

    Article  CAS  Google Scholar 

  15. Forrester, W. C. et al. Genes Dev. 4, 1637–1650 (1990).

    Article  CAS  Google Scholar 

  16. Ferguson, B. M., Brewer, B. J., Reynolds, A. E. & Fangman, W. L. Cell 65, 507–515 (1991).

    Article  CAS  Google Scholar 

  17. Ferguson, B. M. & Fangman, W. L. Cell 68, 333–339 (1992).

    Article  CAS  Google Scholar 

  18. Burhans, W. C. et al. EMBO J. 10, 4351–4360 (1991).

    Article  CAS  Google Scholar 

  19. Seidman, M. M., Levine, A. J. & Weintraub, H. Cell 18, 439–449 (1979).

    Article  CAS  Google Scholar 

  20. Roufa, D. J. & Marchionni, M. A. Proc. natn. Acad. Sci. U.S.A. 79, 1810–1814 (1982).

    Article  ADS  CAS  Google Scholar 

  21. Kioussis, D., Vanin, E., de Lange, T., Flavell, R. A. & Grosveld, F. G. Nature 306, 662–666 (1983).

    Article  ADS  CAS  Google Scholar 

  22. Tarmelli, R. et al. Nucleic Acids Res. 15, 7017–7029 (1986).

    Article  Google Scholar 

  23. Dhar, V., Mager, D., Iqbal, A. & Schildkraut, C. L. Molec. cell. Biol. 8, 4958–4965 (1988).

    Article  CAS  Google Scholar 

  24. Vanin, E. F., Henthorn, P. S., Kioussis, D., Grosveld, F. & Smithies, O. Cell 35, 701–709 (1983).

    Article  CAS  Google Scholar 

  25. Mears, J. G. et al. Proc. natn. Acad. Sci. U.S.A. 75, 1222–1226 (1978).

    Article  ADS  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cellular Biochemistry, Hebrew University Medical School, Jerusalem, 91010, Israel

    D. Kitsberg, S. Selig, I. Keshet & H. Cedar

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  1. D. Kitsberg
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  2. S. Selig
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  3. I. Keshet
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  4. H. Cedar
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Kitsberg, D., Selig, S., Keshet, I. et al. Replication structure of the human & beta;-globin gene domain. Nature 366, 588–590 (1993). https://doi.org/10.1038/366588a0

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