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Site-specific R-loops induce CGG repeat contraction and fragile X gene reactivation.
Lee, Hun-Goo; Imaichi, Sachiko; Kraeutler, Elizabeth; Aguilar, Rodrigo; Lee, Yong-Woo; Sheridan, Steven D; Lee, Jeannie T.
Afiliación
  • Lee HG; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
  • Imaichi S; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
  • Kraeutler E; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
  • Aguilar R; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
  • Lee YW; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
  • Sheridan SD; Center for Quantitative Health Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Psychiatry, Harvard Medical School, Boston, MA 02114, USA.
  • Lee JT; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA. Electronic address: lee@molbio.mgh.harvard.edu.
Cell ; 186(12): 2593-2609.e18, 2023 06 08.
Article en En | MEDLINE | ID: mdl-37209683
ABSTRACT
Here, we describe an approach to correct the genetic defect in fragile X syndrome (FXS) via recruitment of endogenous repair mechanisms. A leading cause of autism spectrum disorders, FXS results from epigenetic silencing of FMR1 due to a congenital trinucleotide (CGG) repeat expansion. By investigating conditions favorable to FMR1 reactivation, we find MEK and BRAF inhibitors that induce a strong repeat contraction and full FMR1 reactivation in cellular models. We trace the mechanism to DNA demethylation and site-specific R-loops, which are necessary and sufficient for repeat contraction. A positive feedback cycle comprising demethylation, de novo FMR1 transcription, and R-loop formation results in the recruitment of endogenous DNA repair mechanisms that then drive excision of the long CGG repeat. Repeat contraction is specific to FMR1 and restores the production of FMRP protein. Our study therefore identifies a potential method of treating FXS in the future.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Expansión de Repetición de Trinucleótido / Síndrome del Cromosoma X Frágil Límite: Humans Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Expansión de Repetición de Trinucleótido / Síndrome del Cromosoma X Frágil Límite: Humans Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos