Research ArticleCell Biology

Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2

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Sci. Signal.  13 Nov 2018:
Vol. 11, Issue 556, eaau0715
DOI: 10.1126/scisignal.aau0715

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Multiple routes to PER2 degradation

The circadian clock is formed by a 24-hour transcriptional-translational feedback loop, wherein the abundance of its core components—CLOCK, BMAL, PER, and CRY—influences cellular biochemistry and responses to stimuli at different times of the day. The E3 ubiquitin ligase β-TrCP promotes the degradation of phosphorylated PER2. Liu et al. found that the E3 ligase MDM2 also ubiquitylated and promoted the degradation of PER2 but did so in a manner that was independent of PER2 phosphorylation. The E3 ligase activity of MDM2 was required for maintaining the proper length of the circadian cycle. In addition to identifying a previously unknown mechanism that contributes to PER2 stability, these findings may have implications in cancer, because MDM2 is an oncoprotein that affects the cellular response to genotoxic stress, and the loss of PER2 makes cells more susceptible to genotoxic stress and animals more prone to develop cancer.

Abstract

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.

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