Circadian period is compensated for repressor protein turnover rates in single cells

• 成果类型: Article
• 署名作者: Gabriel, Christian H.; del Olmo, Marta; Widini, Arunya Rizki; Roshanbin, Rashin; Woyde, Jonas; Hamza, Ebrahim; Gutu, Nica- Nicoleta; Zehtabian, Amin; Ewers, Helge; Granada, Adrian; Herzel, Hanspeter; Kramer, Achim
• 署名单位: Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12564
• DOI: 10.1073/pnas.2404738121
• 发表日期: 2024-08-20
• 关键词: ribosome profiling reveals; clock; degradation; fbxl3; cryptochrome; nucleus; phosphorylation; oscillation; generation; mechanism

摘要

Most mammalian cells have molecular circadian clocks that generate widespread rhythms in transcript and protein abundance. While circadian clocks are robust to fluctuations in the cellular environment, little is known about the mechanisms by which the circadian period compensates for fluctuating metabolic states. Here, we exploit the heterogeneity of single cells both in circadian period and a metabolic parameter-protein stability-to study their interdependence without the need for genetic manipulation. We generated cells expressing key circadian proteins (CRYPTOCHROME1/2 (CRY1/2) and PERIOD1/2 (PER1/2)) as endogenous fusions with fluorescent proteins and simultaneously monitored circadian rhythms and degradation in thousands of single cells. We found that the circadian period compensates for fluctuations in the turnover rates of circadian repressor proteins and uncovered possible mechanisms using a mathematical model. In addition, the stabilities of the repressor proteins are circadian phase dependent and correlate with the circadian period in a phase- dependent manner, in contrast to the prevailing model.