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Nature. 2009 May 21;459(7245):387-392. doi: 10.1038/nature08040. Epub 2009 Apr 29.

Bmi1 regulates mitochondrial function and the DNA damage response pathway.

Author information

1
Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
2
Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
3
Howard Hughes Medical Institute, NIH Research Scholar Program, Bethesda, Maryland 20892, USA.
4
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
5
Division of Molecular Genetics, Netherlands Cancer Institute and Centre for Biomedical Genetics, 1066 CX Amsterdam, The Netherlands.
6
Department of Geriatric Medicine, National Institute for Longevity Sciences National Center for Geriatrics and Gerontology 36-3, Gengo, Morioka, Obu, Aichi 474-8522, Japan.
#
Contributed equally

Abstract

Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1(-/-) phenotype. Here we demonstrate that cells derived from Bmi1(-/-) mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1(-/-) mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.

PMID:
19404261
PMCID:
PMC4721521
DOI:
10.1038/nature08040
[Indexed for MEDLINE]
Free PMC Article

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