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
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.
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 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.
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
