Journal article
A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
Nature genetics, Vol.52(2), pp.146-159
02/2020
DOI: 10.1038/s41588-019-0575-8
PMCID: PMC7043212
PMID: 32060489
Abstract
In many repeat diseases, such as Huntington's disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutSβ. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats.
Details
- Title: Subtitle
- A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
- Creators
- Masayuki Nakamori - The University of OsakaGagan B Panigrahi - Hospital for Sick ChildrenStella Lanni - Hospital for Sick ChildrenTerence Gall-Duncan - University of TorontoHideki Hayakawa - The University of OsakaHana Tanaka - The University of OsakaJennifer Luo - University of TorontoTakahiro Otabe - The University of OsakaJinxing Li - The University of OsakaAkihiro Sakata - The University of OsakaMarie-Christine Caron - Université LavalNiraj Joshi - Université LavalTanya Prasolava - Hospital for Sick ChildrenKaren Chiang - University of TorontoJean-Yves Masson - Université LavalMarc S Wold - University of IowaXiaoxiao Wang - New York Medical CollegeMarietta Y W T Lee - New York Medical CollegeJohn Huddleston - University of WashingtonKatherine M Munson - University of WashingtonScott Davidson - Hospital for Sick ChildrenMehdi Layeghifard - Hospital for Sick ChildrenLisa-Monique Edward - Hospital for Sick ChildrenRichard Gallon - Newcastle UniversityMauro Santibanez-Koref - Newcastle UniversityAsako Murata - The University of OsakaMasanori P Takahashi - The University of OsakaEvan E Eichler - University of WashingtonAdam Shlien - Hospital for Sick ChildrenKazuhiko Nakatani - The University of OsakaHideki Mochizuki - The University of OsakaChristopher E Pearson - University of Toronto
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.52(2), pp.146-159
- DOI
- 10.1038/s41588-019-0575-8
- PMID
- 32060489
- PMCID
- PMC7043212
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Grant note
- R01 ES014737 / NIEHS NIH HHS FRN148910 / CIHR FRN388879 / CIHR R01 HG010169 / NHGRI NIH HHS
- Language
- English
- Date published
- 02/2020
- Academic Unit
- Radiation Oncology; Biochemistry and Molecular Biology
- Record Identifier
- 9984293087502771
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