Molecular mechanism of the repressive phase of the mammalian circadian clock

Area of Science:

• Chronobiology
• Molecular Biology
• Genetics

Background:

• The mammalian circadian clock relies on a transcription-translation feedback loop (TTFL).
• CLOCK-BMAL1 activators and CRY-PER repressors drive this loop.
• Previous models explained CRY repression but not CRY-PER repression in vivo.

Purpose of the Study:

• To elucidate the in vivo mechanism of CRY-PER mediated repression in the mammalian circadian clock.
• To reconcile in vitro and in vivo data regarding PER's role in repression.

Main Methods:

• In vivo and in vitro experiments were used.
• Investigated the recruitment of Casein Kinase 1 delta (CK1δ) by CRY-PER.

Main Results:

• CRY-PER recruits CK1δ to the nucleus, increasing its local concentration at target gene promoters/enhancers.
• This recruitment promotes CLOCK phosphorylation and subsequent dissociation of CLOCK-BMAL1 and CRY from the E-box.
• This mechanism clarifies CRY-PER's role in displacement-type repression.

Conclusions:

• CRY-PER mediates displacement-type repression by recruiting CK1δ.
• This recruitment drives CLOCK-BMAL1 complex dissociation, explaining the dynamic repressive phase of the TTFL.
• Findings clarify PER's function in circadian rhythm regulation.