title: 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.
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jichun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Song
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: In Hye
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Quijano
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Haoqian
authors.initials: H
authors.lastname: Chen
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Long-Yue
authors.initials: LY
authors.lastname: Cao
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Bong-Hyun
authors.initials: BH
authors.lastname: Ahn
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.|Howard Hughes Medical Institute, NIH Research Scholar Program, Bethesda, Maryland 20892, USA.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Kumar
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Xu
authors.affiliation: Division of Molecular Genetics, Netherlands Cancer Institute and Centre for Biomedical Genetics, 1066 CX Amsterdam, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
authors.affiliation: Department of Geriatric Medicine, National Institute for Longevity Sciences National Center for Geriatrics and Gerontology 36-3, Gengo, Morioka, Obu, Aichi 474-8522, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D063150:Polycomb Repressive Complex 1; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects
chemical_list: D000975:Antioxidants; C489421:Bmi1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000111:Acetylcysteine