RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments
- Yiduo Hu1,7,8,
- Steven Raynard2,7,
- Michael G. Sehorn2,9,
- Xincheng Lu1,
- Wendy Bussen2,
- Lu Zheng3,
- Jeremy M. Stark4,
- Ellen L. Barnes1,
- Peter Chi2,
- Pavel Janscak3,
- Maria Jasin5,
- Hannes Vogel6,
- Patrick Sung2,10, and
- Guangbin Luo1,11
- 1 Department of Genetics, Case Comprehensive Cancer Centre, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio 44106, USA;
- 2 Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 3 Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland;
- 4 Department of Radiation Biology, Beckman Research Institute of the City of Hope National Medical Center, Duarte, California 91010, USA;
- 5 Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
- 6 Department of Pathology, Stanford University Medical Center, Stanford, California 94305, USA
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↵7 These authors contributed equally to this work.
Abstract
Members of the RecQ helicase family play critical roles in genome maintenance. There are five RecQ homologs in mammals, and defects in three of these (BLM, WRN, and RECQL4) give rise to cancer predisposition syndromes in humans. RECQL and RECQL5 have not been associated with a human disease. Here we show that deletion of Recql5 in mice results in cancer susceptibility. Recql5-deficient cells exhibit elevated frequencies of spontaneous DNA double-strand breaks and homologous recombination (HR) as scored using a reporter that harbors a direct repeat, and are prone to gross chromosomal rearrangements in response to replication stress. To understand how RECQL5 regulates HR, we use purified proteins to demonstrate that human RECQL5 binds the Rad51 recombinase and inhibits Rad51-mediated D-loop formation. By biochemical means and electron microscopy, we show that RECQL5 displaces Rad51 from single-stranded DNA (ssDNA) in a reaction that requires ATP hydrolysis and RPA. Together, our results identify RECQL5 as an important tumor suppressor that may act by preventing inappropriate HR events via Rad51 presynaptic filament disruption.
Keywords
Footnotes
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↵8 Present addresses: Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA;
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↵9 Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
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↵10 Corresponding authors.
↵10 E-MAIL Patrick.Sung{at}yale.edu; FAX (203) 785-6404.
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↵11 E-MAIL guangbin.luo{at}case.edu; FAX (216) 368-3432.
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Supplemental material is available at http://www.genesdev.org.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1609107
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- Received August 27, 2007.
- Accepted September 27, 2007.
- Copyright © 2007, Cold Spring Harbor Laboratory Press
