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Role of Mismatch Repair Enzymes in GAA•TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells

Du, Jintang and Campau, Erica and Soragni, Elisabetta and Ku, Sherman and Puckett, James W. and Dervan, Peter B. and Gottesfeld, Joel M. (2012) Role of Mismatch Repair Enzymes in GAA•TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells. Journal of Biological Chemistry, 287 (35). pp. 29861-29872. ISSN 0021-9258. PMCID PMC3436184.

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The genetic mutation in Friedreich ataxia (FRDA) is a hyperexpansion of the triplet-repeat sequence GAA•TTC within the first intron of the FXN gene. Although yeast and reporter construct models for GAA•TTC triplet-repeat expansion have been reported, studies on FRDA pathogenesis and therapeutic development are limited by the availability of an appropriate cell model in which to study the mechanism of instability of the GAA•TTC triplet repeats in the human genome. Herein, induced pluripotent stem cells (iPSCs) were generated from FRDA patient fibroblasts after transduction with the four transcription factors Oct4, Sox2, Klf4, and c-Myc. These cells were differentiated into neurospheres and neuronal precursors in vitro, providing a valuable cell model for FRDA. During propagation of the iPSCs, GAA•TTC triplet repeats expanded at a rate of about two GAA•TTC triplet repeats/replication. However, GAA•TTC triplet repeats were stable in FRDA fibroblasts and neuronal stem cells. The mismatch repair enzymes MSH2, MSH3, and MSH6, implicated in repeat instability in other triplet-repeat diseases, were highly expressed in pluripotent stem cells compared with fibroblasts and neuronal stem cells and occupied FXN intron 1. In addition, shRNA silencing of MSH2 and MSH6 impeded GAA•TTC triplet-repeat expansion. A specific pyrrole-imidazole polyamide targeting GAA•TTC triplet-repeat DNA partially blocked repeat expansion by displacing MSH2 from FXN intron 1 in FRDA iPSCs. These studies suggest that in FRDA, GAA•TTC triplet-repeat instability occurs in embryonic cells and involves the highly active mismatch repair system.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2012 The American Society for Biochemistry and Molecular Biology, Inc. Received for publication June 14, 2012; in revised form July 12, 2012; Published July 13, 2012. We thank Dr. Chunping Xu for HPLC and MS analyses of the polyamides. This work was supported, in whole or in part, by National Institutes Health Grant NS062856 from NINDS (to J. M. G.) and Grant GM275681 from NIGMS (to P. B. D.). This work was also supported by a postdoctoral fellowship from the Friedreich's Ataxia Research Alliance (to J. D.) and by a grant from the California Institute for Regenerative Medicine (CIRM).
Funding AgencyGrant Number
National Institute of Neurological Disorders and Stroke (NINDS)NS062856
National Institute of General Medical SciencesGM275681
Friedreich's Ataxia Research AllianceUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)UNSPECIFIED
Subject Keywords:DNA and Chromosomes; Molecular Bases of Disease; DNA-binding Protein; DNA mismatch repair; Induced Pluripotent Stem Cell (iPSC); Neurodegenerative Diseases; Nucleotide Repeat Disease
Issue or Number:35
PubMed Central ID:PMC3436184
Record Number:CaltechAUTHORS:20120927-144905197
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Official Citation:Jintang Du, Erica Campau, Elisabetta Soragni, Sherman Ku, James W. Puckett, Peter B. Dervan, and Joel M. Gottesfeld Role of Mismatch Repair Enzymes in GAA·TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells J. Biol. Chem. 2012 287: 29861-. doi:10.1074/jbc.M112.391961
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:34526
Deposited By: Aucoeur Ngo
Deposited On:10 Oct 2012 21:38
Last Modified:26 Nov 2019 11:15

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