Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Replication stress induces sister-chromatid bridging at fragile site loci in mitosis

Nature Cell Biology volume 11, pages 753–760 (2009)Cite this article

Abstract

Several inherited syndromes in humans are associated with cancer predisposition. The gene products defective in two of these disorders, BLM (a helicase defective in Bloom's syndrome)1 and FANC A–N (defective in Fanconi anaemia)2, associate in a multienzyme complex called BRAFT3. How these proteins suppress tumorigenesis remains unclear, although both conditions are associated with chromosome instability. Here we show that the Fanconi anaemia proteins FANCD2 and FANCI specifically associate with common fragile site loci irrespective of whether the chromosome is broken. Unexpectedly, these loci are frequently interlinked through BLM-associated ultra-fine DNA bridges4 (UFBs) even as cells traverse mitosis. Similarly to fragile site expression5, fragile site bridging is induced after partial inhibition of DNA replication. We propose that, after replication stress, sister chromatids are interlinked by replication intermediates primarily at genetic loci with intrinsic replication difficulties, such as fragile sites. In Bloom's syndrome cells, inefficient resolution of DNA linkages at fragile sites gives rise to increased numbers of anaphase UFBs and micronuclei containing fragile site DNA. Our data have general implications concerning the contribution of fragile site loci to chromosomal instability and tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Replication perturbation induces formation of paired FANCD2/I foci at sister genetic loci.
Figure 2: FANCD2 foci on sister genetic loci show aberrant sister chromatid constrictions and DNA interlinkage.
Figure 3: Figure 3 APH specifically induces the formation of FANCD2-associated UFBs in anaphase cells.
Figure 4: Replication stress induces localization of FANCD2 sister foci to common fragile sites.
Figure 5: BLM is required for the resolution of DNA linkages that arise from common fragile sites.

Similar content being viewed by others

References

  1. Ellis, N. A. et al. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83, 655–666 (1995).

    Article  CAS  Google Scholar 

  2. Wang, W. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nature Rev. Genet. 8, 735–748 (2007).

    Article  CAS  Google Scholar 

  3. Meetei, A. R. et al. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol. Cell. Biol. 23, 3417–3426 (2003).

    Article  CAS  Google Scholar 

  4. Chan, K. L., North, P. S. & Hickson, I. D. BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. EMBO J. 26, 3397–3409 (2007).

    Article  CAS  Google Scholar 

  5. Durkin, S. G. & Glover, T. W. Chromosome fragile sites. Annu. Rev. Genet. 41, 169–192 (2007).

    Article  CAS  Google Scholar 

  6. Mankouri, H. W. & Hickson, I. D. The RecQ helicase–topoisomerase III–Rmi1 complex: a DNA structure-specific 'dissolvasome'? Trends Biochem. Sci. 32, 538–546 (2007).

    Article  CAS  Google Scholar 

  7. German, J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore) 72, 393–406 (1993).

    Article  CAS  Google Scholar 

  8. Baumann, C., Korner, R., Hofmann, K. & Nigg, E. A. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell 128, 101–114 (2007).

    Article  CAS  Google Scholar 

  9. Losada, A. & Hirano, T. Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev. 19, 1269–1287 (2005).

    Article  CAS  Google Scholar 

  10. Arlt, M. F., Casper, A. M. & Glover, T. W. Common fragile sites. Cytogenet. Genome Res. 100, 92–100 (2003).

    Article  CAS  Google Scholar 

  11. Casper, A. M, Nghiem, P, Arlt M.F & Glover T. W. ATR regulates fragile site stability. Cell 13, 779–789 (2002).

    Article  Google Scholar 

  12. Schwartz, M. et al. Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev. 19, 2715–2726 (2005).

    Article  CAS  Google Scholar 

  13. Durkin, S. G. et al. Replication stress induces tumor-like microdeletions in FHIT/FRA3B. Proc. Natl Acad. Sci. USA. 8, 246–251 (2007).

    Google Scholar 

  14. Wang, L. H., Schwarzbraun, T., Speicher, M. R. & Nigg, E. A. Persistence of DNA threads in human anaphase cells suggests late completion of sister chromatid decatenation. Chromosoma 117, 123–135 (2008).

    Article  Google Scholar 

  15. Taniguchi, T. et al. Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109, 459–472 (2002).

    Article  CAS  Google Scholar 

  16. Hirota, T., Gerlich, D., Koch, B., Ellenberg, J. & Peters, J. M. Distinct functions of condensin I and II in mitotic chromosome assembly. J. Cell Sci. 15, 6435–6445 (2004).

    Article  Google Scholar 

Download references

Acknowledgements

We thank members of the Hickson laboratory for helpful discussions, P. McHugh and L. Wu for helpful comments on the manuscript, and P. White for preparation of the manuscript. B. Lopes, P. Jeggo, F. Esashi, A. D'Andrea, G. Brown, E. Nigg and S. Elledge kindly supplied reagents. This work was supported by Cancer Research UK. K.L.C. was supported by the Croucher Foundation (Hong Kong).

Author information

Author notes

  1. Kok Lung Chan

    Present address: Current address: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.,

Authors and Affiliations

  1. Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DS, Oxford, UK

    Kok Lung Chan, Timea Palmai-Pallag, Songmin Ying & Ian D. Hickson

Authors
  1. Kok Lung Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timea Palmai-Pallag
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Songmin Ying
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ian D. Hickson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.L.C., T.P.P. and S.Y. performed experiments and, together with I.D.H., analysed data. K.L.C. and I.D.H. planned experiments and wrote the manuscript.

Corresponding author

Correspondence to Ian D. Hickson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1608 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chan, K., Palmai-Pallag, T., Ying, S. et al. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol 11, 753–760 (2009). https://doi.org/10.1038/ncb1882

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1882

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing