8/11/2019 Final Pieces to the Circadian Clock Puzzle Found
1/3
Home Biology Biotechnology September 14, 2014
Aziz Sancar, M.D., Ph.D., University of North Carolina Health
Care. Credit: UNC School of Medicine
Featured Most shared
Phys.org on facebook
Relevant PhysicsForums posts
More from Physics Forums - Biology
Final pieces to the circadian clockpuzzle foundSep 14, 2014
Researchers at the UNC School of Medicine havediscovered how two
genes Period
and Cryptochrome keep the circadian clocks in all humancells in
time and inproper
rhythm with the 24-hour day, as well as the seasons. The
finding, published today in
the journal Genes and Development, has implications for the
development of drugs for
various diseases such as cancers and diabetes, as well as
conditions such as
metabolic syndrome, insomnia, seasonal affective disorder,
obesity, and even jetlag.
"Discovering how these circadian clockgenesinteract has been a
long-time coming,"
said Aziz Sancar, MD, PhD, Sarah Graham Kenan Professor of
Biochemistry and
Biophysics and senior author of the Genes and Developmentpaper.
"We've known for
a while that four proteins were involved in generating daily
rhythmicity but not exactly
what they did. Now we know how the clock is reset in all cells.
So we have a better idea
of what to expect if we target these proteins with
therapeutics."
In all human cells, there are four genes Cryptochrome, Period,
CLOCK, and BMAL1
that work in unison to control the cyclical changes in human
physiology, such as blood
pressure, body temperature, and rest-sleep cycles. The way in
which these genes
control physiology helps prepare us for the day. This is called
the circadian clock. It
keeps us in proper physiological rhythm. When we try to
fast-forward or rewind the
natural 24-hour day, such as when we fly seven time zones away,
our circadian clocks
don't let us off easy; the genes and proteins need time to
adjust. Jetlag is the feeling of
our cells "realigning" to their new environment and the new
starting point of a solar day.
Previously, scientists found that CLOCK and BMAL1 work in tandem
to kick start the
circadian clock. These genes bind to many other genes and turn
them on to express
proteins. This allows cells, such as brain cells, to behave the
way we need them to at
the start of a day.
Specifically, CLOCK and BMAL1 bind to a pair of genes called
Period and
Cryptochrome and turn them on to express proteins, which after
several modifications
wind up suppressing CLOCK and BMAL1 activity. Then, the Period
and
Cryptochrome proteins are degraded, allowing for the circadian
clock to begin again.
"It's a feedback loop," said Sancar, who discovered Cryptochrome
in 1998. "The
inhibition takes 24 hours. This is why we can see gene activity
go up and then down
throughout the day."
But scientists didn't know exactly how that gene suppression and
protein degradation
Divers sure of new finds from'ancient computer' shipwreck
Sep 15, 2014 18
New Antarctic sea ice recordbutscientists aren't
'confounded'
Sep 15, 2014 35
Physicists design zero-frictionquantum engine 22 hours ago
5
Rules of thumb for climate changeturned upside down Sep 14,
2014
25
Astronomers release most detailedcatalogue ever made of the
visibleMilky Way 23 hours ago 3
Question About Fossils 6 hours ago
Do we have the same DNA as 12-20.000 yearsago? 8 hours ago
How Come this does Not Give Rise to anEpidemic? 13 hours ago
Protein Synthesis. Sep 16, 2014
How imperfect is the human machine Sep 14,
2014
Genetic changes in mosquitoes Sep 09, 2014
Popular
Sign In Register
Physics Nanotechnology Earth Astronomy & Space Chemistry
Biology Technology Other Sciences Medicine & Health
Final pieces to the circadian clock puzzle found 17.09.2014
http://phys.org/news/2014-09-pieces-circadian-clock-puzzle.html
1 / 3
http://www.physicsforums.com/showthread.php?t=769917http://phys.org/editorials/http://phys.org/sort/popular/1m/http://phys.org/news/2014-09-pieces-circadian-clock-puzzle.htmlhttp://phys.org/editorials/http://phys.org/sort/popular/1m/http://phys.org/news/2014-09-pieces-circadian-clock-puzzle.htmlhttp://phys.org/physics-news/http://phys.org/nanotech-news/http://phys.org/earth-news/http://phys.org/space-news/http://phys.org/chemistry-news/http://phys.org/biology-news/http://phys.org/technology-news/http://phys.org/science-news/http://medicalxpress.com/http://phys.org/https://plus.google.com/116557644723047703916/?prsrc=3http://www.facebook.com/physorghttp://twitter.com/physorg_comhttp://twitter.com/physorg_comhttp://www.linkedin.com/company/phys-orghttp://m.phys.org/https://sciencex.com/profile/login/https://sciencex.com/profile/login/#registerhttp://medicalxpress.com/http://phys.org/science-news/http://phys.org/technology-news/http://phys.org/biology-news/http://phys.org/chemistry-news/http://phys.org/space-news/http://phys.org/earth-news/http://phys.org/nanotech-news/http://phys.org/physics-news/http://phys.org/https://sciencex.com/profile/login/#registerhttps://sciencex.com/profile/login/http://m.phys.org/http://www.linkedin.com/company/phys-orghttp://twitter.com/physorg_comhttp://www.facebook.com/physorghttps://plus.google.com/116557644723047703916/?prsrc=3http://phys.org/http://www.physicsforums.com/forumdisplay.php?f=82http://www.physicsforums.com/showthread.php?t=769917http://www.physicsforums.com/showthread.php?t=770697http://www.physicsforums.com/showthread.php?t=771150http://www.physicsforums.com/showthread.php?t=771249http://www.physicsforums.com/showthread.php?t=771313http://www.physicsforums.com/showthread.php?t=771332http://www.facebook.com/physorghttp://phys.org/news/2014-09-astronomers-catalogue-visible-milky.html#ajTabshttp://phys.org/news/2014-09-thumb-climate-upside.html#ajTabshttp://phys.org/news/2014-09-physicists-zero-friction-quantum.html#ajTabshttp://phys.org/news/2014-09-antarctic-sea-ice-recordbut-scientists.html#ajTabshttp://phys.org/news/2014-09-divers-ancient-shipwreck.html#ajTabshttp://phys.org/news/2014-09-pieces-circadian-clock-puzzle.htmlhttp://phys.org/sort/popular/1m/http://phys.org/editorials/http://phys.org/tags/human+cells/http://phys.org/tags/cells/http://phys.org/tags/circadian+clock/http://phys.org/archive/14-09-2014/http://phys.org/biology-news/biotechnology/http://phys.org/biology-news/http://phys.org/
8/11/2019 Final Pieces to the Circadian Clock Puzzle Found
2/3
Journal refe rence:Genes & Development
Provided byUniversity of North Carolina Health Care 4.7 /5 (17
votes)
happened at the back end. In fact, during experiments using one
compound to stifle
Cryptochrome and another drug to hinder Period, other
researchers found inconsistent
effects on the circadian clock, suggesting that Cryptochrome and
Period did not have
the same role. Sancar, a member of the UNC Lineberger
Comprehensive Cancer
Center who studies DNA repair in addition to the circadian
clock, thought the two genes
might have complementary roles. His team conducted experiments
to find out.
Chris Selby, PhD, a research instructor in Sancar's lab, used
two different kinds of
genetics techniques to create the first-ever cell line that
lacked both Cryptochrome and
Period. (Each cell has two versions of each gene. Selby knocked
out all four copies.)
Then Rui Ye, PhD, a postdoctoral fellow in Sancar's lab and
first author of the Genes
and Developmentpaper, put Period back into the new mutant cells.
But Period by itself
did not inhibit CLOCK-BMAL1; it actually had no active function
inside the cells.
Next, Ye put Cryptochrome alone back into the cell line. He
found that Cryptochrome
not only suppressed CLOCK and BMAL1, but it squashed them
indefinitely.
"The Cryptochrome just sat there," Sancar said. "It wasn't
degraded. The circadian
clock couldn't restart."
For the final experiment, Sancar's team added Period to the
cells with Cryptochrome.
As Period's protein accumulated inside cells, the scientists
could see that it began to
remove the Cryptochrome, as well as CLOCK and BMAL1. This led to
the eventual
degradation of Cryptochrome, and then the CLOCK-BMAL1 geneswere
free to restart
the circadian clock anew to complete the 24-hour cycle.
"What we've done is show how the entire clock really works,"
Sancar said. "Now, whenwe screen for drugs that target these
proteins, we know to expect different outcomes
and why we get those outcomes. Whether it's for treatment of
jetlag or seasonal
affective disorderor for controlling and optimizing cancer
treatments, we had to know
exactly how this clock worked."
Previous to this research, in 2010, Sancar's lab found that the
level of an enzyme
called XPA increased and decreased in synchrony with the
circadian clock's natural
oscillations throughout the day. Sancar's team proposed that
chemotherapy would be
most effective when XPA is at its lowest level. For humans,
that's late in the afternoon.
"This means that DNA repair is controlled by the circadian
clock," Sancar said. "It also
means that the circadian clocks in cancer cells could become
targets for cancer drugs
in order to make other therapeutics more effective."
Explore further:Atomic structure of essential circadian clock
proteincomplex determined
Related Stories Recommended for you
Scientists pinpoint link between light signal and
circadianrhythms Dec 29, 2010
In a new paper published this week in the Proceedings of the
National Academy ofSciences, Aziz Sancar, MD, PhD, the Sarah Graham
Kenan Professor of Biochemistryand Biophysics in the UNC School of
Medicine, and his collea ...
Atomic structure of essential circadian clock protein
complexdetermined May 30, 2014
Structural biologists have made important progress towards
better understanding thefunctioning of the circadian clock. The
circadian or inner clock coordinates the sleep-wake rhythm and many
other body processes ...
Researchers determine structure of 'batteries' of the
biologicalclock May 31, 2012
Howard Hughes Medical Institute scientists have determined the
three-dimensionalstructure of two proteins that help keep the
body's clocks in sync. The proteins, CLOCKand BMAL1, bind to each
other to regulate ...
Chrono, the last piece of the circadian clock puzzle? Apr
15,2014
All organisms, from mammals to fungi, have daily cycles
controlled by a tightly regulatedinternal clock, called the
circadian clock. The whole-body circadian clock, influenced bythe
exposure to light, dictates the wake-sleep ...
Bioinformatics profiling identifies a new mammalian clock
gene
New dawn for pasta wheat in Australia 56 minutes ago
The University of Adelaide's durum breeding program today at the
Hart Field Day willrelease a new durum wheat variety called
DBA-Aurora which promises a s tep-change inpotential durum
production in southern Australia.
Bioengineers develop a toolkit for designing more
successfulsynthetic molecules 1 hour ago
(Phys.org) Ever since Robert Hooke first described cells in
1665, scientists have beentrying to figure out what is going on
inside. One of the most exciting modern techniquesinvolves
injecting cells ...
Me, my neuroprocessor, and I: Preparing for a hybrid world
15 hours ago
Around 500 B.C, the Greek historian Herodotus documented the
first recorded use of anartificial limb after encountering a man
with a wooden foot. In 2014 a paraplegic mankicked off the World
Cup soccer ...
Researchers decipher genetic mechanism that makes the
midge invulnerable to harsh conditions 21 hours agoNew
collaborative research published in the journal Nature
Communications byscientists from Japan, Russia and the US contains
the genetic analysis on a species ofAfrican midge, which can
survive a wide ...
Researchers explain mystery of cereal grain defense Sep 15,
2014
Final pieces to the circadian clock puzzle found 17.09.2014
http://phys.org/news/2014-09-pieces-circadian-clock-puzzle.html
2 / 3
http://phys.org/news/2014-09-mystery-cereal-grain-defense.html#nRlvhttp://phys.org/news/2014-09-decipher-genetic-mechanism-midge-invulnerable.html#nRlvhttp://phys.org/news/2014-09-neuroprocessor-hybrid-world.html#nRlvhttp://phys.org/news/2014-09-bioengineers-toolkit-successful-synthetic-molecules.html#nRlvhttp://phys.org/news/2014-09-dawn-pasta-wheat-australia.html#nRlvhttp://medicalxpress.com/news/2014-04-bioinformatics-profiling-mammalian-clock-gene.html#nRlvhttp://phys.org/news/2014-04-chrono-piece-circadian-clock-puzzle.html#nRlvhttp://phys.org/news/2012-05-batteries-biological-clock.html#nRlvhttp://phys.org/news/2014-05-atomic-essential-circadian-clock-protein.html#nRlvhttp://phys.org/news/2010-12-scientists-link-circadian-rhythms.html#nRlvmailto:[email protected]://phys.org/sort/popular/1m/http://www.med.unc.edu/http://phys.org/partners/university-of-north-carolina-health-care/http://phys.org/partners/university-of-north-carolina-health-care/http://genesdev.cshlp.org/http://phys.org/journals/genes-and-development/http://phys.org/journals/genes-and-development/http://phys.org/news/2014-05-atomic-essential-circadian-clock-protein.html#inlRlvhttp://phys.org/tags/seasonal+affective+disorder/http://phys.org/tags/genes/
