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A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
Rosa M Marión1, Katerina Strati, Han Li
1Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid E-28029, Spain.
Nature
|August 12, 2009
Summary
The tumor suppressor p53 prevents the creation of induced pluripotent stem (iPS) cells from damaged cells. Blocking p53 allows the generation of iPS cells with DNA damage and chromosomal abnormalities.
Area of Science:
- Cell Biology
- Genetics
- Stem Cell Research
Background:
- Reprogramming differentiated cells into induced pluripotent stem (iPS) cells is inefficient.
- Cells with short telomeres are resistant to reprogramming, suggesting 'reprogramming barriers' exist.
- These barriers may relate to uncapped telomeres and DNA damage.
Purpose of the Study:
- To investigate the role of p53 in preventing iPS cell reprogramming from cells with DNA damage.
- To determine if p53 acts as a barrier to reprogramming cells with various forms of DNA damage.
Main Methods:
- Utilized mouse and human cell models with induced DNA damage (short telomeres, repair deficiencies, exogenous damage).
- Assessed reprogramming efficiency with and without p53 functional activity.
- Analyzed generated iPS cells for DNA damage and chromosomal stability.
Main Results:
- p53 activation, triggered by DNA damage response, aborts reprogramming via apoptosis.
- Abrogation of p53 function enables efficient reprogramming of damaged cells.
- Generated iPS cells lacking functional p53 exhibit persistent DNA damage and chromosomal aberrations.
Conclusions:
- Cells exhibit increased DNA damage intolerance during reprogramming.
- p53 is essential for preventing the generation of pluripotent cells from suboptimal parental cells.
- p53 acts as a critical safeguard against creating iPS cells with genomic instability.
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