Cancer, hear my battle CRY

Abstract

Circadian clocks are cell-autonomous self-sustaining oscillators that allow organisms to anticipate environmental changes throughout the solar day and persist in nearly every cell examined. Environmental or genetic disruption of circadian rhythms increases the risk of several types of cancer, but the underlying mechanisms are not well understood. Here, we discuss evidence connecting circadian rhythms-with emphasis on the cryptochrome proteins (CRY1/2)-to cancer through in vivo models, mechanisms involving known tumor suppressors and oncogenes, chemotherapeutic efficacy, and human cancer risk.

Keywords: DNA repair; cell cycle; circadian clocks; circadian rhythm; cryptochromes; oncogenes carcinogenesis.

FIGURE 1

Molecular connections between CRY1, CRY2, and cancer-related pathways. The core clock mechanism involves a transcription-translation feedback loop (TTFL) in which the bHLH-PAS transcription factors CLOCK and BMAL1 drive expression of their own repressors, PERs and CRYs (for a more complete description of the molecular clock, see ref.). In the face of growing interest in understanding the mechanistic underpinnings for enhanced cancer risk in people exposed to chronic circadian disruption, several molecular connections between clocks and proteins with established roles in regulating cell growth, DNA repair, and the cellular response to DNA damage have been described. See text for details. Proteins outlined in black exhibit widespread circadian expression at the mRNA level. Brown shading denotes tumor suppressors; bright green shading denotes oncogenes. Substrate receptors for multisubunit E3 ligases are shown in red. Red arrows indicate pathways that lead to ubiquitination and 26S proteasome-mediated degradation. Ub, ubiquitin