RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments.
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.
Hu
Yiduo
Y
Department of Genetics, Case Comprehensive Cancer Centre, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio 44106, USA.
Raynard
Steven
S
Sehorn
Michael G
MG
Lu
Xincheng
X
Bussen
Wendy
W
Zheng
Lu
L
Stark
Jeremy M
JM
Barnes
Ellen L
EL
Chi
Peter
P
Janscak
Pavel
P
Jasin
Maria
M
Vogel
Hannes
H
Sung
Patrick
P
Luo
Guangbin
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D053484:RecQ Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic
D000255:Adenosine Triphosphate; D006657:Histones; D051135:Rad51 Recombinase; D053484:RecQ Helicases; D011994:Recombinant Proteins; C506732:RECQL5 protein, human; C495154:Rad51 protein, mouse; C501069:Recql5 protein, mouse; C475961:gamma-H2AX protein, mouse