|
EMBARGOED FOR 6 P.M.
NSF PR 95-76 - November 2, 1995
Media contact: |
Cheryl Dybas |
(703) 306-1070 |
Program contact: |
Kathie Olsen |
(703) 306-1420 |
This material is available primarily for archival purposes. Telephone
numbers or other contact information may be out of date; please see current
contact information at media
contacts.
Circadian Rhythm Set by Pairing of Two Proteins
The molecular control of the daily cycle known as circadian
rhythm lies in the pairing of two proteins, National
Science Foundation (NSF) scientists report in a trio
of papers in the November 3 issue of the journal Science.
The findings, derived from fruit fly studies, promise
to help scientists better understand human, animal
and plant circadian rhythms. These rhythms influence
cell and body biochemistry, health, aging and behavior.
"Our data show the setting and running of the daily
body clock comes from the delicate affinity of two
proteins," says Michael Young of the National Science
Foundation (NSF) Science and Technology Center for
Biological Timing in Charlottesville, Virginia, who
is also affiliated with Rockefeller University in
New York. Like people, fruit flies have daily rhythms
lasting approximately 24 hours. In 1971, scientists
at the California Institute of Technology discovered
that a fly gene dubbed period (per) was involved in
the clock, but exactly how it worked was unknown.
In 1984, Young and his collaborators at Rockefeller
University and a second group of scientists at Brandeis
University cloned the per gene and characterized the
protein it makes. In 1994, Young's group identified
a second clock gene, dubbed timeless (tim). In the
new studies, Young and collaborators from Rockefeller,
the University of Pennsylvania and Harvard Medical
School cloned the tim gene, determined the order of
nucleic acids in its DNA structure and characterized
the protein it makes, TIM. By investigating what happens
when tim and per are damaged in mutated flies, the
researchers also established how the TIM and PER proteins
together set the body clock.
"The tim and per genes, through the proteins they
make, have a true partnership in operating the body's
clock," says Young. "We found that part of the TIM
protein binds to the PER protein. Once joined, the
proteins enter the cell nucleus, a process that sets
the time and duration of the circadian cycle."
All cells in the fly have per and tim genes, but the
cells in the fly's brain set the body's clock. The
two genes become active at midday. In the cell's nucleus,
the genes' DNA code is transcribed into two RNA molecules,
per RNA and tim RNA, which accumulate over several
hours in the cell.
At dusk, the levels of RNAs peak and only then does
the cell use the RNAs to stockpile PER and TIM proteins.
In the evening, the proteins join and cross into the
cell's nucleus. About four hours before dawn, the
PER and, presumably, TIM proteins in the nucleus reach
their maximum amounts, an achievement that signals
the per and tim genes to stop making the RNA. Near
dawn, the nuclear proteins begin disintegrating, and
the cycle begins again. Throughout the daylight hours
the per and tim genes produce new RNA to make replacement
proteins.
The pace of the clock appears to stem from the gradual,
coordinated accumulation of the tim and per RNAs during
several hours, as well as from the attraction of the
PER and TIM proteins for each other, Young reports.
"The PER and TIM proteins have an affinity for each
other, but it is not a strong link. Only if the two
proteins are available in sufficient quantities do
they begin to bind. Most importantly, the proteins
can only survive and enter the cell nucleus when they
are bound to each other. Therefore, about six to eight
hours lapse between the time of peak RNA accumulation,
which occurs around dusk, and the peak in the nuclear
protein levels, shortly before dawn."
Additional mechanisms and other as-yet-unidentified
proteins also may influence the interaction between
the PER and TIM proteins, which could affect the timing,
Young adds. For example, scientists know that light
affects circadian rhythms. Young also notes that evidence
exists that the PER/TIM protein union is affected
by light. This sensitivity may help explain how body
clocks are reset after a period of jet lag that occurs
as a traveler crosses time zones.
In addition, the scientists are searching for the
genes of the human body clock. "In general, the genes
that control fundamental body mechanisms are passed
on in evolution," Young explains. "Now that we know
the mechanisms in the fly's body clock that produce
the TIM and PER proteins, and the feedback loops involved,
we expect to find a similar process in the body clocks
of humans."
In humans, daily circadian rhythms underlie many functions,
including the sleep/wake cycle, body temperature,
mental alertness, pain sensitivity and hormone production.
In natural conditions, many rhythms have a 24-hour
period related to sunlight, but though light can affect
the rhythm, it does not cause the cycle. In fact,
in the absence of light or other environmental clues,
rhythms continue and most adapt to periods slightly
longer or shorter than 24 hours, Young notes.
Press releases and other information are now available
electronically on NSFnews, a free service available
via the Internet. To subscribe to NSFnews send an
e-mail message to listmanager@nsf.gov. In the body
of the message (not the subject line) type the words
"subscribe nsfnews" and then type your name (not an
e-mail address). For example: Subscribe nsfnews James
Smith. The system will reply with a confirmation via
e-mail. For additional information about NSFnews send
another e-mail message to listmanager@nsf.gov and
in the body of the message type the word "help".
|
|