Michael Alicia K, Harvey Stacy L, Sammons Patrick J, Anderson Amanda P, Kopalle Hema M, Banham Alison H, Partch Carrie L
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
Mol Cell. 2015 Jun 4;58(5):743-54. doi: 10.1016/j.molcel.2015.03.031. Epub 2015 Apr 30.
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.
昼夜节律时钟每天通过bHLH-PAS转录因子CLOCK:BMAL1协调转录调控的全局变化。由其他bHLH-PAS转录因子驱动的通路具有同源阻遏物，可在组织特异性基础上调节活性，但尚未发现CLOCK:BMAL1的同源阻遏物。我们在此表明，癌胚抗原PASD1发挥这一作用来抑制昼夜节律。PASD1在进化上与CLOCK相关，并与CLOCK:BMAL1复合物相互作用以抑制转录激活。PASD1的表达在健康个体中仅限于生殖系组织，但在致癌转化后可在体细胞来源的细胞中被诱导。降低人类癌细胞中的PASD1可显著增加转录振荡的幅度，以产生更强健的昼夜节律。我们的结果描述了一种生殖系特异性蛋白在昼夜节律时钟调节中的功能，并提供了从致癌转化到昼夜节律抑制的分子联系。
