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NONO couples the circadian clock to the cell cycle

机译:NONO将生物钟耦合到细胞周期

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摘要

Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-def icient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-lnk4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-lnk4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.
机译:哺乳动物生物钟将细胞增殖限制在确定的时间窗口内,但这种相互关系的机制和后果尚不完全清楚。以前,我们将多功能核蛋白NONO确定为昼夜节律(PER)蛋白的伴侣。在这里,我们表明它还可以将昼夜节律传递到细胞周期,这种连接对于小鼠伤口愈合非常重要。具体而言,尽管来自NONO缺陷型小鼠的成纤维细胞显示出大约正常的昼夜周期,但它们显示出细胞倍增升高和细胞衰老降低。在分子水平上,NONO与p16-lnk4A细胞周期检查点基因结合,并以PER蛋白依赖性方式增强其昼夜节律激活。 NONO或PER的丢失消除了p16-lnk4A的这种激活和昼夜节律表达,并消除了昼夜节律细胞周期门控。在体内,缺乏NONO导致缺陷的伤口修复。因为在多个昼夜节律缺乏的小鼠品系中也观察到了伤口愈合缺陷,所以我们的结果表明,通过NONO将细胞周期与昼夜节律的偶联可能有助于从组织组织中以时态分离细胞增殖。

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  • 作者单位

    Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland;

    Division of Biochemistry, Department of Medicine, University of Fribourg, 1700 Fribourg, Switzerland;

    Division of Plastic and Reconstructive Surgery, Department of Surgery, University Hospital Zurich, 8006 Zurich, Switzerland;

    Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland;

    Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland;

    Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland;

    Laboratory of Chronobiology, Institute of Medical Immunology, Charite Universitatsmedizin, 10117 Berlin, Germany;

    Division of Biochemistry, Department of Medicine, University of Fribourg, 1700 Fribourg, Switzerland;

    Division of Plastic and Reconstructive Surgery, Department of Surgery, University Hospital Zurich, 8006 Zurich, Switzerland;

    Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    keratinocyte; p54nrb; RNA-binding protein; paraspeckle protein;

    机译:角质形成细胞p54nrb;RNA结合蛋白;散斑蛋白;

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