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© 2015 Elsevier Inc. The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms. The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Michael etal. report that the cancer/testis antigen PASD1 is evolutionarily related to CLOCK and inhibits CLOCK:BMAL1 activity in human cancer.

There is a growing body of evidence that components of the circadian clock are involved in modulation of numerous signaling pathways, and that clock deregulation due to environmental or genetic factors contributes to the development of various pathologies, including cancer. Previous work performed in tissue culture and in in vivo mouse models defined mammalian PERIOD proteins as tumor suppressors, although some experimental inconsistencies (the use of mice on mixed genetic background, lack of sexual discrimination) did not allow a definitive conclusion. To address this issue in a systematic way, we performed a detailed analysis comparing the incidence of tumor development after low-dose ionizing radiation in male and female wild-type, Per1−/−, and Per2−/− mice. We showed that in contrast to previous reports deficiency in either Per1 or Per2 genes by itself does not make mice more tumor-prone; moreover, some of the long-term effects of ionizing radiation in Per2-deficient mice are reminiscent more of accelerated aging rather than tumor-prone phenotype. Our histopathological analysis also revealed significant sexual dimorphism both in the rate of radiation-induced tumorigenesis and in the spectrum of tumors developed, which underscores the importance of using sex-matched experimental groups for in vivo studies. Based on our results, we suggest that the role of PER proteins as bona fide tumor suppressors needs to be reevaluated.