Dataset Information

A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo.

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 MutS?. 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.

SUBMITTER: Nakamori M

PROVIDER: S-EPMC7043212 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo.

Nakamori Masayuki M Panigrahi Gagan B GB Lanni Stella S Gall-Duncan Terence T Hayakawa Hideki H Tanaka Hana H Luo Jennifer J Otabe Takahiro T Li Jinxing J Sakata Akihiro A Caron Marie-Christine MC Joshi Niraj N Prasolava Tanya T Chiang Karen K Masson Jean-Yves JY Wold Marc S MS Wang Xiaoxiao X Lee Marietta Y W T MYWT Huddleston John J Munson Katherine M KM Davidson Scott S Layeghifard Mehdi M Edward Lisa-Monique LM Gallon Richard R Santibanez-Koref Mauro M Murata Asako A Takahashi Masanori P MP Eichler Evan E EE Shlien Adam A Nakatani Kazuhiko K Mochizuki Hideki H Pearson Christopher E CE

Nature genetics 20200214 2

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 ...[more]

PMID: 32060489

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Project description:Disease-associated trinucleotide repeats form secondary DNA structures that interfere with replication and repair. Replication has been implicated as a mechanism that can cause repeat expansions and contractions. However, because structure-forming repeats are also replication barriers, it has been unclear whether the instability occurs due to slippage during normal replication progression through the repeat, slippage or misalignment at a replication stall caused by the repeat, or during subsequent replication of the repeat by a restarted fork that has altered properties. In this study, we have specifically addressed the fidelity of a restarted fork as it replicates through a CAG/CTG repeat tract and its effect on repeat instability. To do this, we used a well-characterized site-specific replication fork barrier (RFB) system in fission yeast that creates an inducible and highly efficient stall that is known to restart by recombination-dependent replication (RDR), in combination with long CAG repeat tracts inserted at various distances and orientations with respect to the RFB. We find that replication by the restarted fork exhibits low fidelity through repeat sequences placed 2-7 kb from the RFB, exhibiting elevated levels of Rad52- and Rad8ScRad5/HsHLTF-dependent instability. CAG expansions and contractions are not elevated to the same degree when the tract is just in front or behind the barrier, suggesting that the long-traveling Polδ-Polδ restarted fork, rather than fork reversal or initial D-loop synthesis through the repeat during stalling and restart, is the greatest source of repeat instability. The switch in replication direction that occurs due to replication from a converging fork while the stalled fork is held at the barrier is also a significant contributor to the repeat instability profile. Our results shed light on a long-standing question of how fork stalling and RDR contribute to expansions and contractions of structure-forming trinucleotide repeats, and reveal that tolerance to replication stress by fork restart comes at the cost of increased instability of repetitive sequences.

Dataset Information

A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo.

Publications

A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo.

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