title: RTEL1 inhibits trinucleotide repeat expansions and fragility.
abstract: Human RTEL1 is an essential, multifunctional helicase that maintains telomeres, regulates homologous recombination, and helps prevent bone marrow failure. Here, we show that RTEL1 also blocks trinucleotide repeat expansions, the causal mutation for 17 neurological diseases. Increased expansion frequencies of (CTG⋅CAG) repeats occurred in human cells following knockdown of RTEL1, but not the alternative helicase Fbh1, and purified RTEL1 efficiently unwound triplet repeat hairpins in vitro. The expansion-blocking activity of RTEL1 also required Rad18 and HLTF, homologs of yeast Rad18 and Rad5. These findings are reminiscent of budding yeast Srs2, which inhibits expansions, unwinds hairpins, and prevents triplet-repeat-induced chromosome fragility. Accordingly, we found expansions and fragility were suppressed in yeast srs2 mutants expressing RTEL1, but not Fbh1. We propose that RTEL1 serves as a human analog of Srs2 to inhibit (CTG⋅CAG) repeat expansions and fragility, likely by unwinding problematic hairpins.
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Newcastle Road, Galway, Ireland.
authors.forename: Aisling
authors.initials: A
authors.lastname: Frizzell
authors.affiliation: Department of Biology, Tufts University, Medford, MA 02155, USA.
authors.forename: Jennifer H G
authors.initials: JH
authors.lastname: Nguyen
authors.affiliation: DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
authors.forename: Mark I R
authors.initials: MI
authors.lastname: Petalcorin
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Newcastle Road, Galway, Ireland; NCBES Galway Neuroscience Centre, National University of Ireland Galway, Newcastle Road, Galway, Ireland.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Turner
authors.affiliation: DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
authors.affiliation: Department of Biology, Tufts University, Medford, MA 02155, USA.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Freudenreich
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Newcastle Road, Galway, Ireland; NCBES Galway Neuroscience Centre, National University of Ireland Galway, Newcastle Road, Galway, Ireland. Electronic address: bob.lahue@nuigalway.ie.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lahue
mesh_terms: D002873:Chromosome Fragility; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D004268:DNA-Binding Proteins; C100023:HLTF protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; C532890:RTEL1 protein, human; D004265:DNA Helicases