Ticking time bombs: connections between circadian clocks and cancer

Abstract

Connections between mammalian circadian and cell division cycles have been postulated since the early 20th century, and epidemiological and genetic studies have linked disruption of circadian clock function to increased risk of several types of cancer. In the past decade, it has become clear that circadian clock components influence cell growth and transformation in a cell-autonomous manner. Furthermore, several molecular mechanistic connections have been described in which clock proteins participate in sensing DNA damage, modulating DNA repair, and influencing the ubiquitination and degradation of key players in oncogenesis (c-MYC) and tumor suppression (p53).

Keywords: CRYs; PERs; cancer; cell cycle; circadian clock.

Figure 1.. Molecular connections between circadian clocks, cell cycle, and cancer drivers.

( a) The core mammalian circadian clock transcription-translation feedback loop (TTFL) involves the positive factors CLOCK and BMAL1 activating expression of their own repressors PERs and CRYs. This clock mechanism also drives daily rhythmic expression of so-called clock-controlled genes (ccgs), including P21 ( Cdkn1a), Wee1, Ccnb1, Ccnd1, Myc, and Xpa mRNAs. ( b) PER and CRY modulate post-translational regulation of P53 and c-MYC. PER2 blocks MDM2 ubiquitination of P53, while CRY2 stimulates ubiquitination of c-MYC by SCF(FBXL3). HAUSP removes polyubiquitin chains from CRY1 as well as from P53. Lightning bolts represent processes that are stimulated by DNA damage. Additional connections are described in the text.