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DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 110(10)
- Publication Year :
- 2013
-
Abstract
- DNA damage leads to a halt in proliferation owing to apoptosis or senescence, which prevents transmission of DNA alterations. This cellular response depends on the tumor suppressor p53 and functions as a powerful barrier to tumor development. Adult stem cells are resistant to DNA damage-induced apoptosis or senescence, however, and how they execute this response and suppress tumorigenesis is unknown. We show that irradiation of hematopoietic and mammary stem cells up-regulates the cell cycle inhibitor p21, a known target of p53, which prevents p53 activation and inhibits p53 basal activity, impeding apoptosis and leading to cell cycle entry and symmetric self-renewing divisions. p21 also activates DNA repair, limiting DNA damage accumulation and self-renewal exhaustion. Stem cells with moderate DNA damage and diminished self-renewal persist after irradiation, however. These findings suggest that stem cells have evolved a unique, p21-dependent response to DNA damage that leads to their immediate expansion and limits their long-term survival.
- Subjects :
- Senescence
Cyclin-Dependent Kinase Inhibitor p21
Mice, 129 Strain
DNA Repair
DNA damage
DNA repair
Stem cell theory of aging
Apoptosis
Biology
medicine.disease_cause
Mice
Mammary Glands, Animal
medicine
Animals
Mice, Knockout
Multidisciplinary
Cell Cycle Checkpoints
Cell cycle
Biological Sciences
Hematopoietic Stem Cells
Cell biology
Up-Regulation
Mice, Inbred C57BL
Adult Stem Cells
Cancer research
Female
Stem cell
Tumor Suppressor Protein p53
Carcinogenesis
Cell Division
Adult stem cell
DNA Damage
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 110
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....43c897057bdcebd8750341f90af3a0f6