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Cancer/Testis Antigen PASD1 Silences the Circadian Clock
Alicia K Michael1, Stacy L Harvey1, Patrick J Sammons1
1Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Abstract:
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.
Insights
The cancer/testis antigen PASD1 suppresses daily circadian rhythms by interacting with the CLOCK:BMAL1 complex. Oncogenic transformation can induce PASD1, linking cancer to disrupted circadian rhythms.
Area of Science:
- Molecular biology
- Chronobiology
- Cancer research
Background:
- The circadian clock regulates daily gene expression via the CLOCK:BMAL1 transcription factor.
- Homologous repressors modulate other bHLH-PAS transcription factor pathways, but none were known for CLOCK:BMAL1.
Purpose of the Study:
- To identify a repressor for the CLOCK:BMAL1 complex.
- To investigate the role of the cancer/testis antigen PASD1 in circadian rhythm regulation.
- To explore the link between oncogenic transformation and circadian rhythm disruption.
Main Methods:
- Investigated the interaction between PASD1 and the CLOCK:BMAL1 complex.
- Analyzed PASD1 expression patterns in healthy and cancerous tissues.
- Assessed the impact of PASD1 reduction on circadian transcriptional oscillations in human cancer cells.
Main Results:
- PASD1 acts as a repressor of circadian rhythms by interacting with CLOCK:BMAL1.
- PASD1 expression is normally restricted to germline tissues but is induced in somatic cells during oncogenic transformation.
- Reducing PASD1 levels in human cancer cells enhanced the amplitude of circadian transcriptional oscillations.
Conclusions:
- PASD1 is a novel, germline-specific repressor of the circadian clock.
- PASD1 provides a molecular link between oncogenic transformation and the suppression of circadian rhythms.
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