Bmi1 regulates mitochondrial function and the DNA damage response pathway

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.

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Figure 1: The absence of Bmi1 increases ROS levels and alters mitochondrial function.
Figure 2: Antioxidant treatment rescues Bmi1 -/- thymocytes.
Figure 3: Activation of the DDR pathway in Bmi1 -/- thymocytes occurs through a redox-sensitive pathway.
Figure 4: Inhibition of the DDR pathway by Chk2 deletion rescues multiple defects in Bmi1 -/- mice.

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Acknowledgements

We are grateful to M. Clarke for providing the initial supply of Bmi1-/- mice, to J. Moss for the gift of anti-PARP antibodies and to M. Daniels and the NHLBI electron microscope core for their assistance. This work was supported by funding from the NIH intramural program and the Ellison Medical Foundation.

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Correspondence to Liu Cao or Toren Finkel.

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Liu, J., Cao, L., Chen, J. et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459, 387–392 (2009). https://doi.org/10.1038/nature08040

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