Cancer/Testis Antigen PASD1 Silences the Circadian Clock.
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.
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Alicia K
AK
Michael
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Stacy L
SL
Harvey
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Patrick J
PJ
Sammons
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
Amanda P
AP
Anderson
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Hema M
HM
Kopalle
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
Alison H
AH
Banham
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Center for Circadian Biology, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: cpartch@ucsc.edu.
Carrie L
CL
Partch
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000502:physiology*; D034961:Antigens, Nuclear / Q000737:chemistry / Q000502:physiology*; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D017124:Conserved Sequence; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D013737:Testis / Q000378:metabolism
D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D000951:Antigens, Neoplasm; D034961:Antigens, Nuclear; C515845:PASD1 protein, human; D056926:CLOCK Proteins; C538943:CLOCK protein, human