2012 Winner: Inhibition of the Primary Circadian Transcription Factor by PASD1, a Cancer Testis Antigen

Project Information
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.
Students
  • Patrick Jack Sammons (Eight)
Mentors