Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 52

although to validate this requires further characterization of the molecular conse-
quences of these polymorphisms. Investigating the diversity of human genotypes
and the phenotypic effects of these genetic variations shall advance our understanding
of the function of the circadian clock and how we can employ the clock to improve our
overall health.

1. INTRODUCTION

The circadian clock regulates daily rhythms of behavior and physiol-
ogy in organisms ranging from bacteria to human, 1 with the daily sleep and
wake cycle in animals being one of the most prominent functions regulated
by the clock. An intact clock enables the organism to adjust its biological
processes to anticipate daily changes in the environment, whereas a
disrupted clock underlies various disorders and/or diseases. 2
Our understanding of the human molecular clock is largely based
on studies in rodents and in vitro . The molecular clock consists of a series
of transcriptional/posttranscriptional feedback loops with Clock and Bmal1
at the center of the loops. 3 CLOCK/BMAL1 dimers activate the transcrip-
tion of three Period genes ( Per1 , 2 , and 3 ) and two Cryptochrome genes ( Cry1
and Cry2 ). PER and CRY heterodimerize and translocate into the nucleus,
inhibiting the transcriptional activity of CLOCK/BMAL1. In a second
loop, CLOCK/BMAL1 activates the transcription of retinoic acid-related
orphan receptors, Rev-erba . The former inhibits, whereas the latter

activates transcription of Bmal1 . In certain tissues, neuronal PAS domain
protein 2 (NPAS2) functions as a CLOCK analog. 4 CLOCK and BMAL1
are also believed to drive the expression of Dec1 and Dec2 , which function to
repress the transactivation of CLOCK/BMAL1 at clock-gene promoters. 5,6
In addition, DBP and E4BP4 are clock-controlled positive and negative reg-
ulators, respectively, of D-boxes in the promoter regions of clock genes. 7-9
TIMELESS may also function in the clock by associating with PER/CRY
and inhibiting CLOCK/BMAL1-stimulated transcription of Per . 10
Besides transcriptional control, posttranslational modifications also play a
critical role in setting the speed of clock. Casein kinase 1 epsilon (CK1 e ) and
casein kinase 1 delta (CK1 d ) impinge on the negative limb of the feedback
loop by phosphorylating PERs, resulting in enhanced protein turnover and
nuclear translocation, which in turn affects the transactivation by CLOCK/
BMAL1. 11 Mutation in Ck1e

and Rora

dramatically shortens the period of circadian
rhythms in both hamster and mouse. 12,13 Consistently, a mutation in CK1d