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

Tidball AM, Neely MD, Chamberlin R, Aboud AA, Kumar KK, Han B, Bryan MR, Aschner M, Ess KC, Bowman AB
PLoS One. 2016 11 (3): e0150372

PMID: 26982737 · PMCID: PMC4794230 · DOI:10.1371/journal.pone.0150372

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.

MeSH Terms (16)

Adult Aged Cells, Cultured DNA Damage Gene Knockdown Techniques Genomic Instability Humans Huntington Disease Induced Pluripotent Stem Cells Karyotyping Middle Aged Nucleic Acid Synthesis Inhibitors Signal Transduction Tumor Suppressor Protein p53 Young Adult Zinostatin

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