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PMID: 18957201 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

RTEL1 maintains genomic stability by suppressing homologous recombination.

Cell ·Vol. 135 ·No. 2 ·2008-10-17 ·Pages 261-71

Barber LJ, Youds JL, Ward JD, McIlwraith MJ, O'Neil NJ, Petalcorin MI, Martin JS, Collis SJ, Cantor SB, Auclair M, Tissenbaum H, West SC, Rose AM, Boulton SJ

Abstract

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.

MeSH Terms
Animals Caenorhabditis elegans/enzymology,genetics,metabolism Caenorhabditis elegans Proteins/genetics,metabolism DNA/metabolism DNA Helicases/genetics,metabolism DNA Repair Genomic Instability Humans Mutation Recombination, Genetic Saccharomyces cerevisiae/enzymology Saccharomyces cerevisiae Proteins/metabolism
Chemicals
Caenorhabditis elegans Proteins Saccharomyces cerevisiae Proteins SRS2 protein, S cerevisiae DNA RTEL1 protein, human rcq-5 protein, C elegans DNA Helicases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Barber Louise J
DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
Youds Jillian L
Ward Jordan D
McIlwraith Michael J
O'Neil Nigel J
Petalcorin Mark I R
Martin Julie S
Collis Spencer J
Cantor Sharon B
Auclair Melissa
Tissenbaum Heidi
West Stephen C
Rose Ann M
Boulton Simon J
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2008.08.016
Published
2008-10-17
Pages
261-71
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3726190
Subset
IM
Grants
NIA NIH HHS · R01 AG025891 · United States
NIA NIH HHS · R01 AG025891-01 · United States
NIA NIH HHS · R01 AG031237 · United States
Cancer Research UK · United Kingdom
Corrections
CommentIn
PMID: 18957197
External Links
PubMed source DOI: 10.1016/j.cell.2008.08.016 PMC Full Text View journal details
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