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

Leonard Wu and Ian D. Hickson ()
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Leonard Wu: Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
Ian D. Hickson: Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital

Nature, 2003, vol. 426, issue 6968, 870-874

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature02253

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