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The Bloom's syndrome helicase suppresses crossing over during homologous recombination

Nature volume 426, pages 870–874 (2003)Cite this article

Abstract

Mutations in BLM, which encodes a RecQ helicase, give rise to Bloom's syndrome, a disorder associated with cancer predisposition and genomic instability1. A defining feature of Bloom's syndrome is an elevated frequency of sister chromatid exchanges2. These arise from crossing over of chromatid arms during homologous recombination, a ubiquitous process that exists to repair DNA double-stranded breaks and damaged replication forks. Whereas crossing over is required in meiosis, in mitotic cells it can be associated with detrimental loss of heterozygosity. BLM forms an evolutionarily conserved complex with human topoisomerase IIIα (hTOPO IIIα)3,4, which can break and rejoin DNA to alter its topology. Inactivation of homologues of either protein leads to hyper-recombination in unicellular organisms5. Here, we show that BLM and hTOPO IIIα together effect the resolution of a recombination intermediate containing a double Holliday junction. The mechanism, which we term double-junction dissolution, is distinct from classical Holliday junction resolution and prevents exchange of flanking sequences. Loss of such an activity explains many of the cellular phenotypes of Bloom's syndrome. These results have wider implications for our understanding of the process of homologous recombination and the mechanisms that exist to prevent tumorigenesis.

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Figure 1: Generation of a substrate containing a double HJ.
Figure 2: BLM and hTOPO IIIα can convert DHJ into circular products.
Figure 3: The generation of circular products is specific for the combination of BLM and hTOPO IIIα.
Figure 4: Analysis of the reaction mechanism for the generation of circular products.

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Acknowledgements

We thank H. Goulaouic, J.-F. Riou and S. Matson for proteins, and members of the Genomic Integrity Group for useful discussions. We also thank J. Haber, S. C. West, E. Louis, P. McHugh and R. Borts for comments on the manuscript, and J. Haber for communicating results before publication. This work is supported by the Cancer Research UK.

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

    Leonard Wu & Ian D. Hickson

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  1. Leonard Wu
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  2. Ian D. Hickson
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Correspondence to Ian D. Hickson.

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The authors declare that they have no competing financial interests.

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Wu, L., Hickson, I. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426, 870–874 (2003). https://doi.org/10.1038/nature02253

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