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Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in

Taisuke Kinoshita1, Go Nagamatsu, Takeo Kosaka

  • 1Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582, Japan.

Biochemical and Biophysical Research Communications
|March 10, 2011
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) plays a role in somatic cell reprogramming, reducing efficiency but not preventing induced pluripotent stem cell (iPSC) generation. ATM-deficient iPSCs maintain pluripotency despite accumulating genomic abnormalities.

Area of Science:

  • Cell Biology
  • Genetics
  • Stem Cell Research

Background:

  • Somatic cell reprogramming to induced pluripotent stem cells (iPSCs) can expose cells to DNA damage.
  • The tumor suppressor gene p53's inactivation enhances reprogramming but increases chromosomal abnormalities.
  • Ataxia-telangiectasia mutated (ATM) is crucial for DNA double-strand break response and may influence reprogramming.

Purpose of the Study:

  • To investigate the function of ATM in the somatic cell reprogramming process.
  • To assess the impact of ATM deficiency on reprogramming efficiency and the characteristics of resulting iPSCs.

Main Methods:

  • Reprogramming of ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs).
  • Analysis of reprogramming efficiency, proliferation, gene expression, and differentiation capacity of ATM-KO iPSCs.
  • Karyotyping and assessment of genomic stability in ATM-KO iPSCs over passages.

Main Results:

  • Reprogramming efficiency was significantly reduced in ATM-KO TTFs.
  • ATM-KO iPSCs were successfully generated, exhibiting similar proliferation and gene expression profiles to wild-type (WT) iPSCs and embryonic stem (ES) cells.
  • ATM-KO iPSCs demonstrated differentiation potential into all three germ layers.
  • ATM-KO iPSCs accumulated abnormal genome structures with continuous passaging but retained pluripotency for at least 20 passages.

Conclusions:

  • ATM participates in somatic cell reprogramming, influencing efficiency.
  • ATM deficiency does not prevent the generation of functional iPSCs but leads to genomic instability over time.
  • The role of ATM in reprogramming is not essential for generating pluripotent stem cells.

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