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

Andrew M. Tidball, M. Diana Neely, Reed Chamberlin, Asad A. Aboud, Kevin K. Kumar, Bingying Han, Miles R. Bryan, Michael Aschner, Kevin C. Ess, Aaron B. Bowman

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e0150372
JournalPLoS One
Volume11
Issue number3
DOIs
StatePublished - 2016

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Induced Pluripotent Stem Cells
Genomic Instability
Huntington Disease
Stem cells
DNA damage
genomics
DNA Damage
fibroblasts
chromosome aberrations
DNA
Fibroblasts
karyotyping
cell lines
mutation
Chromosomal Instability
induced pluripotent stem cells
genotype
Karyotype
Automatic teller machines
Chromosome Aberrations

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Tidball, A. M., Neely, M. D., Chamberlin, R., Aboud, A. A., Kumar, K. K., Han, B., ... Bowman, A. B. (2016). Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells. PLoS One, 11(3), e0150372. https://doi.org/10.1371/journal.pone.0150372

Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells. / Tidball, Andrew M.; Neely, M. Diana; Chamberlin, Reed; Aboud, Asad A.; Kumar, Kevin K.; Han, Bingying; Bryan, Miles R.; Aschner, Michael; Ess, Kevin C.; Bowman, Aaron B.

In: PLoS One, Vol. 11, No. 3, 2016, p. e0150372.

Research output: Contribution to journalArticle

Tidball, AM, Neely, MD, Chamberlin, R, Aboud, AA, Kumar, KK, Han, B, Bryan, MR, Aschner, M, Ess, KC & Bowman, AB 2016, 'Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells', PLoS One, vol. 11, no. 3, pp. e0150372. https://doi.org/10.1371/journal.pone.0150372
Tidball, Andrew M. ; Neely, M. Diana ; Chamberlin, Reed ; Aboud, Asad A. ; Kumar, Kevin K. ; Han, Bingying ; Bryan, Miles R. ; Aschner, Michael ; Ess, Kevin C. ; Bowman, Aaron B. / Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells. In: PLoS One. 2016 ; Vol. 11, No. 3. pp. e0150372.
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