TY - JOUR
T1 - A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
AU - Nakamori, Masayuki
AU - Panigrahi, Gagan B.
AU - Lanni, Stella
AU - Gall-Duncan, Terence
AU - Hayakawa, Hideki
AU - Tanaka, Hana
AU - Luo, Jennifer
AU - Otabe, Takahiro
AU - Li, Jinxing
AU - Sakata, Akihiro
AU - Caron, Marie Christine
AU - Joshi, Niraj
AU - Prasolava, Tanya
AU - Chiang, Karen
AU - Masson, Jean Yves
AU - Wold, Marc S.
AU - Wang, Xiaoxiao
AU - Lee, Marietta Y.W.T.
AU - Huddleston, John
AU - Munson, Katherine M.
AU - Davidson, Scott
AU - Layeghifard, Mehdi
AU - Edward, Lisa Monique
AU - Gallon, Richard
AU - Santibanez-Koref, Mauro
AU - Murata, Asako
AU - Takahashi, Masanori P.
AU - Eichler, Evan E.
AU - Shlien, Adam
AU - Nakatani, Kazuhiko
AU - Mochizuki, Hideki
AU - Pearson, Christopher E.
N1 - Funding Information:
This work was partially supported by the Canadian Institutes of Health Research (FRN388879, J.-Y.M. and FRN148910, C.E.P.), Natural Sciences and Engineering Research Council (RGPIN-2016-08355, C.E.P.), Muscular Dystrophy Canada (C.E.P.), Tribute Communities (C.E.P.), The Petroff Family Fund (C.E.P.), The Kazman Family Fund (C.E.P.), The Marigold Foundation (C.E.P.), The National Center of Neurology and Psychiatry (29-4, M.N.), a JSPS KAKENHI Grant-in-Aid for Young Scientists (Start-up A, 24890110 and 25713034, M.N.), Scientific Research (B, 16H05321, M.N.) and Specially Promoted Research (26000007, K.N.), the Cancer Research UK Catalyst Award (C569/A24991, R.G.), the US National Institutes of Health (2 R01 ES014737, M.Y.W.T.L.) and a US National Institutes of Health (NIH) grant (HG010169 to E.E.E.). E.E.E. is an investigator of the Howard Hughes Medical Institute, A. Shlien holds the Canada Research Chair in Childhood Cancer Genomics, J.-Y.M. holds the Fonds de Recherche de Santé Québec Chair in Genome Stability, and C.E.P. holds the Canada Research Chair in Disease-Associated Genome Instability. We acknowledge the technical support of R. Manabe, K. Hayashi, P. Wang, L. Yu, M. Mirceta, N. Thakkar, I. Panigrahi, D. Ripsman, H. Adhikary, S. Bérubé, Y. Coulombe, A. Couturier, M. Scofield Sorensen and K. Hoekzema. We acknowledge TCAG (SickKids) for expedited sequencing.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-019-0575-8
DO - 10.1038/s41588-019-0575-8
M3 - Article
C2 - 32060489
AN - SCOPUS:85079488498
SN - 1061-4036
VL - 52
SP - 146
EP - 159
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -