The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat-containing proteins (β-TrCPs), which are F-box-containing proteins that function as substrate recognition subunits of the SCFβ-TRCP ubiquitin ligase complex. However, this mode of regulating PER2 stability falls short of explaining the persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery. We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. Deregulation of MDM2 plays a major role in oncogenesis by contributing to the accumulation of genomic and epigenomic alterations that favor tumor development. MDM2-mediated PER2 turnover was important for defining the circadian period length in mammalian cells, a finding that emphasizes the connection between the circadian clock and cancer. Our results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis.

中文翻译：

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癌蛋白和泛素连接酶MDM2对PERIOD2降解和昼夜节律的不同控制。

昼夜节律时钟依赖于翻译后修饰来设置核心调节成分降解的时间，从而驱动时钟进程。靶向降解时钟成分的泛素修饰酶主要识别磷酸化的底物。昼夜节律时钟组件PERIOD 2（PER2）的降解是由含β-转导蛋白重复蛋白（β-TrCPs）的磷酸特异性识别介导的，β-TrCPs是具有F-box的蛋白，其功能是SCFβ的底物识别亚基-TRCP泛素连接酶复合物。但是，这种调节PER2稳定性的模式不足以解释在缺乏磷依赖性PER2降解机制功能元件的生物系统中报道的持续振荡表型。我们将PER2鉴定为泛素连接酶小鼠双分钟2同源物（MDM2）的先前未知的底物，并发现MDM2以不依赖于PER2磷酸化的方式靶向PER2降解。MDM2的失调通过促进有利于肿瘤发展的基因组和表观基因组改变的积累而在肿瘤发生中起主要作用。MDM2介导的PER2转换对于确定哺乳动物细胞中昼夜节律的周期长度很重要，这一发现强调了昼夜节律与癌症之间的联系。我们的结果不仅将MDM2特定底物的范围扩大到细胞周期以外，还包括昼夜节律成分，而且将以前未知的时钟调节剂鉴定为可药物化的节点，而该节点在肿瘤发生期间常常被失调。