Explanation of Nobel Prize in Physiology or Medicine 2017- Molecular Mechanisms Controlling the Circadian Rhythm

The Nobel Prize in Physiology or Medicine 2017 was awarded jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discoveries of molecular mechanisms controlling the circadian rhythm.

What is Circadian rhythm? (Circa: around; dies: day in Latin)

To adapt to such changes in light and temperature, organisms have evolved an internal biological clock that anticipates day/night cycles and helps them optimize their physiology and behavior. This internally generated daily rhythm is known as circadian rhythm

Circadian Rhythm was first identified in plants (Mimosa). Later this internal biological clock was found to be present in all organisms including unicellular organisms, fungus, plants and animals.

Period gene First gene identified dealing with Circadian Rhythm

Period gene was the first gene identified dealing with circadian rhythm. (Konopka and Benzer, 1971)

This gene was later cloned and sequenced  by Jeffrey Hall and
Michael Rosbash,, and Michael Young

Period (PER)  gene, mRNA & protein:

cycling of period mRNA and period protein
PER protein shuttles btw nucleus and cytoplasm
Accumulation of PER protein resulted in the reduction of period mRNA expression (negative autoregulatory feedback)
The peak of period mRNA levels
occurred early in the night, several hours before the peak in PER protein abundance.

TIM protein : coded by timeless gene can directly bind to PER protein. The interaction is critical for
PER protein nuclear accumulation and repression of the period gene.

How is Period and TIM gene activated?

 CLOCK (CLK) and CYCLE (CYC) protein interact with each other, and bind to specific elements in the period and timeless genes, thereby positively regulating their transcription.

TIM and PER act as negative regulators of CLK activity, and by this, the circadian feedback loop is closed.

How the transcription (Per mRNA) and translation (Per protein) synthesis is delayed or How Per & Tim protein is degraded?

DOUBLETIME protein a kinase : coded by double time (DBT) gene that phosphorylates PER
and increases its degradation. Light can activate the protein product of the cryptochrome cry gene (CRY) and promote its binding to TIM, leading to its degradation in the When morning arrives, TIM is degraded, leaving PER vulnerable to phosphorylation by DBT and subsequent degradation.

Transcription-Translation Feedback Loop (TTFL).

  The molecular mechanism that regulates Circadian rhythm is called Transcription-Translation Feedback Loop (TTFL).

 Accumulation of PER protein resulted in the reduction of period mRNA expression (negative autoregulatory feedback) called as translational feed back and transcription activators of Per gene, CLOCK (CLK) and CYCLE (CYC) is inhibited by TIM-PER protein accumulation in nucleus.

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