Replication stress induces sister-chromatid bridging at fragile site loci in mitosis (original) (raw)

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.

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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).

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  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

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  1. Kok Lung Chan
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  2. Timea Palmai-Pallag
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  3. Songmin Ying
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  4. Ian D. Hickson
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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.

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Correspondence toIan D. Hickson.

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The authors declare no competing financial interests.

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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

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