Bmi1 regulates mitochondrial function and the DNA damage response pathway.
Bmi1 regulates mitochondrial function and the DNA damage response pathway.
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DOI：
10.1038/nature08040
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发表时间：
2009-05-21
期刊：
影响因子：
64.8
通讯作者：
Finkel T
中科院分区：
文献类型：
--
作者：
Liu J;Cao L;Chen J;Song S;Lee IH;Quijano C;Liu H;Keyvanfar K;Chen H;Cao LY;Ahn BH;Kumar NG;Rovira II;Xu XL;van Lohuizen M;Motoyama N;Deng CX;Finkel T
缺乏Polycomb抑制子Bmi 1的小鼠会出现许多异常，包括干细胞自我更新的严重缺陷、胸腺细胞成熟的改变和寿命缩短。先前的工作已经暗示Ink 4a/Arf（也称为Cdkn 2a）基因座的去抑制介导Bmi 1-/-表型的许多方面。在这里，我们证明了来自Bmi 1-/-小鼠的细胞也有受损的线粒体功能，细胞内活性氧水平显着增加，随后参与DNA损伤反应途径。此外，通常在Bmi 1-/-小鼠中观察到的许多缺陷在用抗氧化剂N-乙酰半胱氨酸进行药物治疗或通过Chk 2（也称为Chek 2）缺失对DNA损伤反应途径进行遗传破坏后得到改善。这些结果表明，Bmi 1在维持线粒体功能和氧化还原稳态方面具有意想不到的作用，并表明Polycomb蛋白家族可以协调调节细胞代谢与干细胞和祖细胞功能。
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.