Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Gene Knockdown Techniques* ; Genomic Instability*; Huntington Disease/*pathology ; Induced Pluripotent Stem Cells/*pathology ; Tumor Suppressor Protein p53/*genetics; Adult ; Aged ; Cells, Cultured ; DNA Damage ; Humans ; Huntington Disease/genetics ; Karyotyping ; Middle Aged ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Signal Transduction/drug effects ; Young Adult ; Zinostatin/pharmacology
    • Abstract:
      Alterations in DNA damage response and repair have been observed in Huntington's disease (HD). We generated induced pluripotent stem cells (iPSC) from primary dermal fibroblasts of 5 patients with HD and 5 control subjects. A significant fraction of the HD iPSC lines had genomic abnormalities as assessed by karyotype analysis, while none of our control lines had detectable genomic abnormalities. We demonstrate a statistically significant increase in genomic instability in HD cells during reprogramming. We also report a significant association with repeat length and severity of this instability. Our karyotypically normal HD iPSCs also have elevated ATM-p53 signaling as shown by elevated levels of phosphorylated p53 and H2AX, indicating either elevated DNA damage or hypersensitive DNA damage signaling in HD iPSCs. Thus, increased DNA damage responses in the HD genotype is coincidental with the observed chromosomal aberrations. We conclude that the disease causing mutation in HD increases the propensity of chromosomal instability relative to control fibroblasts specifically during reprogramming to a pluripotent state by a commonly used episomal-based method that includes p53 knockdown.
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    • Grant Information:
      ES010563 United States ES NIEHS NIH HHS; U54 HD083211 United States HD NICHD NIH HHS; T32 GM007347 United States GM NIGMS NIH HHS; R01 ES016931 United States ES NIEHS NIH HHS; ES016931 United States ES NIEHS NIH HHS; R01 NS078289 United States NS NINDS NIH HHS; R01 ES010563 United States ES NIEHS NIH HHS; F31 NS077632 United States NS NINDS NIH HHS; T32 GM07347 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (Nucleic Acid Synthesis Inhibitors)
      0 (Tumor Suppressor Protein p53)
      9014-02-2 (Zinostatin)
    • Publication Date:
      Date Created: 20160317 Date Completed: 20160725 Latest Revision: 20201215
    • Publication Date:
      20231215
    • Accession Number:
      PMC4794230
    • Accession Number:
      10.1371/journal.pone.0150372
    • Accession Number:
      26982737