Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Abstract

The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G 2 -M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. ©2010 AACR.

Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers

“…Because mutations in protein-coding genes are considered to be a causative factor in carcinogenesis (Ionov et al 1993;Markowitz et al 1995;Perucho 1996;Rampino et al 1997;Alhopuro et al 2010), we filtered MS mutations in gene regions (both coding sequences [CDSs] and UTRs) from the identified total deletions (Supplemental Table S2, S3). The number of deletion mutations in gene regions was four-to sixfold higher in MSI-H gastric cancer cell lines and primary tissues than MSS samples.…”

Circadian angiogenesis

“…Furthermore, genetic disruption of the circadian signalling pathways may be a factor behind disease-development in humans (131)(132)(133). Particularly in cancer cells, which have an unstable genome, mutations in the circadian clock genes are not uncommon (133,134), and therefore the circadian clock could be locally Figure 2 Scheme indicating our hypothesis on how disruptions in circadian rhythmicity increase the risk of disease, alternatively poorer response to treatment. Various types of circadian disruption such as shift-work, jet-lag, sleep disorders or genetic polymorphisms negatively affect important physiological functions, including rhythm generation by the central pacemaker in the SCN, metabolism, immune function, physical activity, cardiovascular functions and intestinal functions.…”

“…Also other types of sleep disorders as well as stress and worries brought about increasing demands from the society on our personal performance may influence the circadian clock and cause disease (130). Furthermore, genetic disruption of the circadian signalling pathways may be a factor behind disease-development in humans (131)(132)(133). Particularly in cancer cells, which have an unstable genome, mutations in the circadian clock genes are not uncommon (133,134), and therefore the circadian clock could be locally Figure 2 Scheme indicating our hypothesis on how disruptions in circadian rhythmicity increase the risk of disease, alternatively poorer response to treatment.…”

Perchance to dream: understanding the complexities of sleep

“…13 Many of these genes also seem to contribute to the relationship between sleep and psychiatric conditions. For example, the transcription factor clock regulates the expression of numerous other circadian genes.…”

“…For example, the transcription factor clock regulates the expression of numerous other circadian genes. 13 Certain CLOCK variants seem to increase the risk of early, middle and late insomnia as well as influencing changes in sleep patterns during treatment with antidepressants. PER3 polymorphisms are associated with worse mood in the evening and DSPS.…”