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.

Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins

“…Nonetheless, we cannot exclude a modest effect of Bmi1 deletion on DNA repair, because Bmi1 has been reported to be involved in DNA repair initiation (37,38). In contrast, there is recent evidence that Bmi1 loss increases oxidative stress in neurons (39) as well as in other cell types (40). In consequence, our results show that Bmi1 deletion can have a dual effect on cell survival, making investigations on the direct and indirect Bmi1 targets a priority for future studies, to generate appropriate tools for therapy.…”

Epigenetic regulation of aging stem cells

“…Whether altered BMI1 function during aging may partly explain the observed accumulation of DNA damage markers in aging stem cell populations (Rossi et al, 2007a) is not yet known, but BMI1 may provide an important molecular link between chromatin regulation and response to DNA damage. Interestingly, loss of Chk2 also rescues the premature aging phenotype of Bmi1 À/À mice and thereby links improved progenitor cell function with overall extended organismal lifespan (Liu et al, 2009). These findings suggest that modulators of chromatin state, such as BMI1, are pivotal for maintaining the ability of adult stem cells to integrate and respond to environmental stresses during aging.…”

“…protein CHK2 (Liu et al, 2009). Deletion of Chk2 in Bmi1 À/À mice restores hematopoietic stem and progenitor cell function and enhances progenitor cell proliferation (Liu et al, 2009).…”

“…Deletion of Chk2 in Bmi1 À/À mice restores hematopoietic stem and progenitor cell function and enhances progenitor cell proliferation (Liu et al, 2009). Whether altered BMI1 function during aging may partly explain the observed accumulation of DNA damage markers in aging stem cell populations (Rossi et al, 2007a) is not yet known, but BMI1 may provide an important molecular link between chromatin regulation and response to DNA damage.…”

Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex

“…PRC2 provides a substrate for PRC1 recruitment but also has repressive activities independent of PRC1 in several systems (12,15). Both polycomb complexes repress expression of functionally diverse gene sets, including developmentally important transcription factors, several classes of cell-cycle regulators, and genes involved in mitochondrial function and the generation of reactive oxygen species (16)(17)(18).…”