Article
- The EMBO Journal (2005) 24, 2679 - 2687
- doi:10.1038/sj.emboj.7600740
Published online: 30 June 2005
Subject Category:
The HRDC domain of BLM is required for the dissolution of double Holliday junctions
Leonard Wu1, Kok Lung Chan1, Christine Ralf1, Douglas A Bernstein2, Patrick L Garcia3, Vilhelm A Bohr4, Alessandro Vindigni5, Pavel Janscak3, James L Keck2 and Ian D Hickson1
- Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
- Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI, USA
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
- Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, MD, USA
- International Centre for Genetic Engineering and Biotechnology, Padriciano, Trieste, Italy
Correspondence to:
Ian D Hickson, Cancer Research UK Laboratories, Oxford Cancer Centre, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. Tel.: +44 1865 222 417; Fax: +44 1865 222 431; E-mail: ian.hickson@cancer.org.uk
Received 19 April 2005; Accepted 10 June 2005
Abstract
Bloom's syndrome is a hereditary cancer-predisposition disorder resulting from mutations in the BLM gene. In humans, BLM encodes one of five members of the RecQ helicase family. One function of BLM is to act in concert with topoisomerase III
(TOPO III) to resolve recombination intermediates containing double Holliday junctions by a process called double Holliday junction dissolution, herein termed dissolution. Here, we show that dissolution is highly specific for BLM among human RecQ helicases and critically depends upon a functional HRDC domain in BLM. We show that the HRDC domain confers DNA structure specificity, and is required for the efficient binding to and unwinding of double Holliday junctions, but not for the unwinding of a simple partial duplex substrate. Furthermore, we show that lysine-1270 of BLM, which resides in the HRDC domain and is predicted to play a role in mediating interactions with DNA, is required for efficient dissolution.
Keywords:
- Bloom's syndrome,
- Holliday junction resolution,
- HRDC domain,
- RecQ DNA helicases,
- topoisomerase III
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