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RTEL1 Maintains Genomic Stability By Suppressing Homologous Recombination

L. Barber, J. Youds, Jordan D. Ward, M. McIlwraith, N. O’Neil, M. I. Petalcorin, J. S. Martin, S. Collis, S. Cantor, Melissa Auclair, H. Tissenbaum, S. West, A. Rose, S. Boulton
Published 2008 · Biology, Medicine

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Homologous recombination (HR) is an important conserved process for DNA repair and ensures maintenance of genome integrity. Inappropriate HR causes gross chromosomal rearrangements and tumorigenesis in mammals. In yeast, the Srs2 helicase eliminates inappropriate recombination events, but the functional equivalent of Srs2 in higher eukaryotes has been elusive. Here, we identify C. elegans RTEL-1 as a functional analog of Srs2 and describe its vertebrate counterpart, RTEL1, which is required for genome stability and tumor avoidance. We find that rtel-1 mutant worms and RTEL1-depleted human cells share characteristic phenotypes with yeast srs2 mutants: lethality upon deletion of the sgs1/BLM homolog, hyperrecombination, and DNA damage sensitivity. In vitro, purified human RTEL1 antagonizes HR by promoting the disassembly of D loop recombination intermediates in a reaction dependent upon ATP hydrolysis. We propose that loss of HR control after deregulation of RTEL1 may be a critical event that drives genome instability and cancer.
This paper references
10.1038/nature01585
The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments
X. Veaute (2003)
10.1016/J.DNAREP.2003.07.003
Deficiency of Caenorhabditis elegans RecQ5 homologue reduces life span and increases sensitivity to ionizing radiation.
Y. S. Jeong (2003)
The effect of temperature and parental age on recombination and nondisjunction in Caenorhabditis
A. M. Rose (1979)
10.1128/MCB.25.8.3127-3139.2005
RAD-51-Dependent and -Independent Roles of a Caenorhabditis elegans BRCA2-Related Protein during DNA Double-Strand Break Repair
J. S. Martin (2005)
10.1128/MCB.12.7.3224
Semidominant suppressors of Srs2 helicase mutations of Saccharomyces cerevisiae map in the RAD51 gene, whose sequence predicts a protein with similarities to procaryotic RecA proteins.
A. Aboussekhra (1992)
10.1128/JB.134.3.958-966.1978
Recombinant levels of Escherichia coli K-12 mutants deficient in various replication, recombination, or repair genes.
J. Zieg (1978)
10.1046/j.1365-2958.1997.6011973.x
uvrD mutations enhance tandem repeat deletion in the Escherichia coli chromosome via SOS induction of the RecF recombination pathway
H. Bierne (1997)
10.1006/JMBI.2000.4180
Reconstitution of the strand invasion step of double-strand break repair using human Rad51 Rad52 and RPA proteins.
M. McIlwraith (2000)
10.1038/ng778
Genes required for ionizing radiation resistance in yeast
C. B. Bennett (2001)
10.1128/MCB.24.11.5016-5027.2004
Multiple Genetic Pathways Involving the Caenorhabditis elegans Bloom's Syndrome Genes him-6, rad-51, and top-3 Are Needed To Maintain Genome Stability in the Germ Line
C. Wicky (2004)
10.1016/j.molcel.2007.11.033
The Srs2 helicase activity is stimulated by Rad51 filaments on dsDNA: implications for crossover incidence during mitotic recombination.
P. Dupaigne (2008)
10.1074/JBC.M201612200
The Novel Human DNA Helicase hFBH1 Is an F-box Protein*
J. Kim (2002)
Mutations in recombinational repair and in checkpoint control genes suppress the lethal combination of srs2Delta with other DNA repair genes in Saccharomyces cerevisiae.
H. Klein (2001)
10.1073/PNAS.0402105101
Ca2+ activates human homologous recombination protein Rad51 by modulating its ATPase activity.
D. Bugreev (2004)
10.1042/BST0290196
Double-strand-break-induced homologous recombination in mammalian cells.
R. Johnson (2001)
10.1128/MCB.25.18.8084-8096.2005
The F-Box DNA Helicase Fbh1 Prevents Rhp51-Dependent Recombination without Mediator Proteins
F. Osman (2005)
10.1093/HMG/11.18.2189
Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines.
A. Mohindra (2002)
10.1177/001088046600700305
The
H. Peretz (1966)
10.1128/JB.139.3.866-876.1979
Metabolic suppressors of trimethoprim and ultraviolet light sensitivities of Saccharomyces cerevisiae rad6 mutants.
C. Lawrence (1979)
10.1101/GAD.1609107
RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments.
Yiduo Hu (2007)
Analysis of mitotic and meiotic defects in Saccharomyces cerevisiae SRS2 DNA helicase mutants.
F. Palladino (1992)
10.1128/MCB.25.13.5738-5751.2005
Srs2 and Sgs1 DNA Helicases Associate with Mre11 in Different Subcomplexes following Checkpoint Activation and CDK1-Mediated Srs2 Phosphorylation
I. Chiolo (2005)
10.1093/NAR/21.14.3205
Antipairing and strand transferase activities of E. coli helicase II (UvrD).
P. Morel (1993)
10.1016/S0092-8674(03)00886-9
Srs2 and Sgs1–Top3 Suppress Crossovers during Double-Strand Break Repair in Yeast
G. Ira (2003)
10.1016/j.cell.2004.05.026
Regulation of Murine Telomere Length by Rtel An Essential Gene Encoding a Helicase-like Protein
Hao Ding (2004)
10.1073/pnas.132275199
Transcriptional response of Saccharomyces cerevisiae to DNA-damaging agents does not identify the genes that protect against these agents
G. W. Birrell (2002)
10.1093/NAR/29.14.2963
Involvement of Schizosaccharomyces pombe Srs2 in cellular responses to DNA damage.
S. Wang (2001)
10.1016/j.cell.2013.04.054
A DNA Integrity Network in the Yeast Saccharomyces cerevisiae
X. Pan (2006)
10.1128/MCB.01641-07
DOG-1 Is the Caenorhabditis elegans BRIP1/FANCJ Homologue and Functions in Interstrand Cross-Link Repair
J. Youds (2007)
10.1073/PNAS.0603791103
A Caenorhabditis elegans tissue model of radiation-induced reproductive cell death.
J. Weidhaas (2006)
10.1038/nature01577
DNA helicase Srs2 disrupts the Rad51 presynaptic filament
L. Krejčí (2003)
10.1016/S0960-9822(01)00604-2
C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein
S. Ahmed (2001)
10.1016/S1534-5807(03)00232-6
Synaptonemal complex assembly in C. elegans is dispensable for loading strand-exchange proteins but critical for proper completion of recombination.
M. Colaiácovo (2003)
10.1128/MCB.00963-07
The Human F-Box DNA Helicase FBH1 Faces Saccharomyces cerevisiae Srs2 and Postreplication Repair Pathway Roles
I. Chiolo (2007)
10.1016/0092-8674(93)90586-F
Cell
AC Tose (1993)
10.1534/genetics.106.056879
Homologous Recombination Is Required for Genome Stability in the Absence of DOG-1 in Caenorhabditis elegans
J. Youds (2006)
The genetics of Caenorhabditis elegans.
S. Brenner (1974)
10.1093/NAR/17.18.7211
RADH, a gene of Saccharomyces cerevisiae encoding a putative DNA helicase involved in DNA repair. Characteristics of radH mutants and sequence of the gene.
A. Aboussekhra (1989)
10.1016/S0092-8674(02)00615-3
Cancer Susceptibility and the Functions of BRCA1 and BRCA2
A. Venkitaraman (2002)
10.1038/ncb1555
HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability
S. Collis (2007)
10.1016/S0092-8674(01)00536-0
Mus81-Eme1 Are Essential Components of a Holliday Junction Resolvase
M. N. Boddy (2001)
10.1101/GAD.1609007
Novel pro- and anti-recombination activities of the Bloom's syndrome helicase.
D. Bugreev (2007)
10.1074/JBC.M402586200
Role of ATP Hydrolysis in the Antirecombinase Function of Saccharomyces cerevisiae Srs2 Protein*
L. Krejci (2004)
10.1007/BF00267368
Hyper-recombination in uvrD mutants of Escherichia coli K-12
H. Arthur (2004)
10.1016/J.DNAREP.2006.06.010
C. elegans FANCD2 responds to replication stress and functions in interstrand cross-link repair.
S. Collis (2006)
10.1038/cr.2008.1
Homologous recombination in DNA repair and DNA damage tolerance
X. Li (2008)
10.1093/BIOMET/46.3-4.441
CONFIDENCE INTERVALS FOR THE EXPECTATION OF A POISSON VARIABLE
E. L. Crow (1959)
Recombinant replication protein A: expression, complex formation, and functional characterization.
L. A. Henricksen (1994)
10.1101/GAD.1370505
The Fanconi Anemia/BRCA pathway: new faces in the crowd.
R. Kennedy (2005)
10.1016/S0921-8777(97)00028-1
Purification of human Rad51 protein by selective spermidine precipitation.
P. Baumann (1997)
10.1073/pnas.252652399
Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication
F. Fabre (2002)
10.1016/S0733-8635(18)30101-3
Bloom's syndrome
J. German (1995)
Genetic control of intrachromosomal recombination in Saccharomyces cerevisiae. I. Isolation and genetic characterization of hyper-recombination mutations.
A. Aguilera (1988)
J. Biol. Chem
10.1073/PNAS.97.3.1230
Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster.
C. Bai (2000)
10.1051/medsci/200319121171
[Caenorhabditis elegans].
M. Labouesse (2003)
The hyper-gene conversion hpr5-1 mutation of Saccharomyces cerevisiae is an allele of the SRS2/RADH gene.
L. Rong (1991)
10.1021/BI0018640
Binding and melting of D-loops by the Bloom syndrome helicase.
A. J. van Brabant (2000)
10.1146/ANNUREV.GENET.38.072902.091500
Recombination proteins in yeast.
B. O. Krogh (2004)
10.1038/76055
Homologous recombination is responsible for cell death in the absence of the Sgs1 and Srs2 helicases
S. Gangloff (2000)
10.1016/J.CELL.2005.12.036
A DNA Integrity Network in the Yeast Saccharomyces cerevisiae
X. Pan (2006)
10.1126/SCIENCE.286.5448.2339
Requirement of yeast SGS1 and SRS2 genes for replication and transcription.
S. Lee (1999)
10.1242/dev.01136
A Werner syndrome protein homolog affects C. elegans development, growth rate, life span and sensitivity to DNA damage by acting at a DNA damage checkpoint
Se-Jin Lee (2004)
10.1038/ncb1212
The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair
C. Sørensen (2005)
The Effect of Temperature and Parental Age on Recombination and Nondisjunction in CAENORHABDITIS ELEGANS.
A. Rose (1979)
10.1038/nrm1359
T-loops and the origin of telomeres
T. D. Lange (2004)
10.1093/nar/gkl258
Mobile D-loops are a preferred substrate for the Bloom's syndrome helicase
C. Bachrati (2006)
10.1007/s00412-003-0237-5
Genetic and cytological characterization of the recombination protein RAD-51 in Caenorhabditis elegans
Arno Alpi (2003)
10.1038/ng928
Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA
I. Cheung (2002)
10.1128/MCB.25.18.8074-8083.2005
Role of the Schizosaccharomyces pombe F-Box DNA Helicase in Processing Recombination Intermediates
T. Morishita (2005)
quirement of yeast SGS 1 and SRS 2 genes for replication and transcription
S. K. Lee (1999)
10.1126/SCIENCE.1091317
Global Mapping of the Yeast Genetic Interaction Network
A. Tong (2004)
10.1016/j.cell.2004.10.011
Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres
R. Wang (2004)
10.1128/MCB.02043-06
Cooperative Roles of Vertebrate Fbh1 and Blm DNA Helicases in Avoidance of Crossovers during Recombination Initiated by Replication Fork Collapse
Masaoki Kohzaki (2007)



This paper is referenced by
10.3390/genes10010010
Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA
W. Leung (2018)
10.4161/cc.29251
Regulation and roles of Cdc7 kinase under replication stress
Masayuki Yamada (2014)
10.1128/MCB.00471-09
Fbh1 Limits Rad51-Dependent Recombination at Blocked Replication Forks
A. Lorenz (2009)
10.1007/s00411-009-0261-9
Heavy ions, radioprotectors and genomic instability: implications for human space exploration
Jaroslaw Dziegielewski (2010)
10.1093/nar/gkz587
An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability
J. Mitxelena (2019)
10.1016/j.bbadis.2009.02.008
Telomeres do the (un)twist: helicase actions at chromosome termini.
A. Chávez (2009)
Analysis of chromosomal rearrangements after replication restart
Saed Mohebi (2014)
10.1128/MCB.00117-17
PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice
Ayako L Mochizuki (2017)
10.1093/nar/gky218
An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability
J. Mitxelena (2018)
The evolution of recombination and genomic structures: a modeling approach
Alexandra Popa (2011)
Novel strategies for diagnosis of glioblastoma multiforme
A. M. Sonabend (2010)
10.1016/j.cell.2010.08.006
SnapShot: Homologous Recombination in DNA Double-Strand Break Repair
Gerard Mazón (2010)
10.3390/genes11030255
History of DNA Helicases
R. Brosh (2020)
10.1080/15476286.2015.1094596
The molecular genetics of the telomere biology disorders
A. Bertuch (2016)
10.1164/rccm.201408-1510OC
Rare variants in RTEL1 are associated with familial interstitial pneumonia.
J. Cogan (2015)
10.1038/s41580-019-0152-0
DNA double-strand break repair-pathway choice in somatic mammalian cells
R. Scully (2019)
10.1111/pace.13284
Association of genetic variation in telomere‐related SNP and telomerase with ventricular arrhythmias in ischemic cardiomyopathy
V. Sawhney (2018)
10.1038/ng.3615
Genomic analysis of snub-nosed monkeys (Rhinopithecus) identifies genes and processes related to high-altitude adaptation
L. Yu (2016)
10.1016/j.molcel.2009.11.009
Rep Provides a Second Motor at the Replisome to Promote Duplication of Protein-Bound DNA
C. P. Guy (2009)
Clinical Cancer esearch ing , Diagnosis , Prognosis etic Risk Profiles Identify Different R ecular Etiologies for Glioma
M J Mark (2010)
10.1016/j.molcel.2010.09.019
The DNA damage response: making it safe to play with knives.
Alberto Ciccia (2010)
10.1007/978-1-4419-8044-1_5
Caenorhabditis elegans Radiation Responses
Aymeric P. Bailly (2011)
The cancer-testis gene, MEIOB, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency
Yayun Gu (2020)
10.1001/archneurol.2010.4
New insights into susceptibility to glioma.
Y. Liu (2010)
10.1371/journal.pgen.1006394
The RTR Complex Partner RMI2 and the DNA Helicase RTEL1 Are Both Independently Involved in Preserving the Stability of 45S rDNA Repeats in Arabidopsis thaliana
Sarah Röhrig (2016)
10.1371/journal.pgen.1007701
The tumor suppressor BRCA1-BARD1 complex localizes to the synaptonemal complex and regulates recombination under meiotic dysfunction in Caenorhabditis elegans
Qianyan Li (2018)
Association between regulator of telomere elongation helicase 1 polymorphism and susceptibility to glioma.
Shujun Pei (2015)
Repair and genetic consequences of DNA double strand breaks during animal development
Bennie Lemmens (2014)
10.1007/s00204-009-0423-1
Telomere maintenance: all’s well that ends well
L. Liew (2009)
10.1016/j.febslet.2010.05.023
Metabolism of postsynaptic recombination intermediates
C. A. Adelman (2010)
10.1016/j.mrfmmm.2016.02.003
FANCJ at the FORK.
S. Cantor (2016)
10.1038/nrm2587
Cancer biology: Another string to the bow
Gemma K. Alderton (2008)
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