TALEN-Induced Double-Strand Break Repair of CTG Trinucleotide Repeats

Cell Reports
Valentine MosbachGuy-Franck Richard

Abstract

Trinucleotide repeat expansions involving CTG/CAG triplets are responsible for several neurodegenerative disorders, including myotonic dystrophy and Huntington's disease. Because expansions trigger the disease, contracting repeat length could be a possible approach to gene therapy for these disorders. Here, we show that a TALEN-induced double-strand break was very efficient at contracting expanded CTG repeats in yeast. We show that RAD51, POL32, and DNL4 are dispensable for double-strand break repair within CTG repeats, the only required genes being RAD50, SAE2, and RAD52. Resection was totally abolished in the absence of RAD50 on both sides of the break, whereas it was reduced in a sae2Δ mutant on the side of the break containing the longest repeat tract, suggesting that secondary structures at double-strand break ends must be removed by the Mre11-Rad50 complex and Sae2. Following the TALEN double-strand break, single-strand annealing occurred between both sides of the repeat tract, leading to repeat contraction.

Citations

Jul 6, 2018·Current Genetics·Valentine MosbachGuy-Franck Richard
Nov 27, 2018·Nucleic Acids Research·Lionel GellonCatherine H Freudenreich
Feb 21, 2019·The Journal of Gene Medicine·Ali ZareiSeyed Mohammad Bagher Tabei
Jul 31, 2019·International Journal of Molecular Sciences·Renée H L RaaijmakersDerick G Wansink
Mar 11, 2020·Frontiers in Molecular Biosciences·Alexandra C VítorSérgio F de Almeida
Jun 25, 2018·Biology Methods and Protocols·David ViterboGuy-Franck Richard
Oct 6, 2020·Current Opinion in Systems Biology·Sanjay VasheeCarole Lartigue
Feb 14, 2021·Journal of Huntington's Disease·Vanessa C Wheeler, Vincent Dion
Dec 7, 2020·Current Opinion in Genetics & Development·Rebecca E Brown, Catherine H Freudenreich
Dec 12, 2018·Genes, Chromosomes & Cancer·Simran Kaushal, Catherine H Freudenreich
Sep 1, 2021·Current Opinion in Genetics & Development·Erica J Polleys, Catherine H Freudenreich
Jan 17, 2020·Molecular Therapy. Nucleic Acids·Alex J FélixVéronique Noé
Nov 11, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Seren MarshThomas C Roberts

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