title: DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions.
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.
authors: Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.
authors: Alessandra
authors: A
authors: Insinga
authors: Angelo
authors: A
authors: Cicalese
authors: Mario
authors: M
authors: Faretta
authors: Barbara
authors: B
authors: Gallo
authors: Luisa
authors: L
authors: Albano
authors: Simona
authors: S
authors: Ronzoni
authors: Laura
authors: L
authors: Furia
authors: Andrea
authors: A
authors: Viale
authors: Pier Giuseppe
authors: PG
authors: Pelicci
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000502:physiology / Q000528:radiation effects; D002455:Cell Division / Q000502:physiology* / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000528:radiation effects; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53