Explanation of Nobel Prize in Physiology or Medicine 2017 Circadian Rhythm Explained Topic: Discoveries of Molecular Mechanisms Controlling the Circadian Rhythm Content: What is Circadian Rhythm? Circadian Rhythm in Humans Molecular Mechanism -Transcription-Translation Feedback Loop (TTFL) Genes involved in Circadian Rhythm- PERIOD gene, TIM gene, CLK gene, CYCLE gene, CRY gene and DOUBLETIME protein

1. Discoveries of Molecular Mechanisms
Controlling the Circadian Rhythm
Nobel Prize in Physiology or Medicine 2017
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2. Affiliation at the time of the
award:
University of Maine,
Maine, ME, USA
Affiliation at the time of
the award:
Brandeis University,
Waltham, MA, USA,
H H M I
Affiliation at the time of
the award:
Rockefeller University,
New York, USA
Jeffrey C. Hall Michael Rosbash Michael W. Young
Nobel Prize Winners 2017
Physiology or Medicine
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3. What is Circadian Rhythm?
Mimosa plant leaves opens towards the sun during day time and close at dusk
Experiment: Mimosa plant kept in constant darkness for several days to check the rhythm is due
to sunlight and temperature
Result: Mimosa plant kept in constant darkness for several days also showed the same daily
rhythm suggesting the existence of a cell autonomous clock that can maintain
the biological rhythm even under constant conditions. This is the Circadian rhythm
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French astronomer Jean
Jacques d’Ortous de Mairan( 1729)

4. 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
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5. Molecular Mechanism of Circadian Rhythm
(Konopka and Benzer, 1971)
showing change in
the normal 24h
cycle of pupal
eclosion and
locomotor activity
Identified a common mutated gene in all three flies
Period gene, the first gene identified dealing with circadian rhythm.
This gene was later cloned and sequenced by Jeffrey Hall and
Michael Rosbash,, and Michael Young
PERIOD gene: the first gene identified
Seymour Benzer
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6. Transcription-Translation Feedback Loop (TTFL)
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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.
Per gene
Per mRNA
Per protein
Tim protein
Nucleus
Cytoplasm

7. Transcription-Translation Feedback Loop
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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
Per gene
Per mRNA
Per protein
CLK: CLOCK
CYC: CYCLE
Nucleus
Cytoplasm

8. Transcription-Translation Feedback Loop (TTFL)
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How the transcription (Per mRNA)
and translation (Per protein)
synthesis is delayed?
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.
Per gene
Per mRNA
Per protein
Translational feedback
Transcriptional feedback
CLK: CLOCK
CYC: CYCLE
CRY: Cryptochrome
Nucleus
Cytoplasm

9. Importance of this Discovery

10. Please Don’t Forget to
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