Inhibition of the Primary Circadian Transcription Factor by PASD1, a Cancer Testis Antigen
Physical and Biological Sciences
Biochemistry Program
The circadian rhythm synchronizes the physiological processes of mammals to the 24
hour light-dark cycle of the solar day. This mechanism is driven by an oscillator with an
interlocking and self-sustaining feedback loop with positive and negative arms that control
expression of ~15% of the genome. The CLOCK and BMAL1 heterodimer constitute the positive
arm by driving transcription of PER and CRY, which act as the negative arm by directly
repressing CLOCK:BMAL1 transactivation and thereby their own expression; after degradation
of PER and CRY, this process begins anew. Here we provide evidence that the uncharacterized
cancer testis antigen, PASD1, is a potent and specific inhibitor of CLOCK:BMAL1 transcriptional
activity in mammals. PASD1 is homologous to the core transcription factor CLOCK and localizes
to the nucleus. Using mechanistic studies, we identify regions important for repression. As a
cancer testis antigen, PASD1 expression is normally restricted to gametogenic tissues but
upregulated in many forms of cancer. Its expression in human tumor samples is anti-correlated
to the expression of core circadian genes. Our results suggest that PASD1 acts as a dominant
negative protein to represses circadian rhythmicity in mammalian tissues, and may have a role
in oncogenesis.
