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Sleep and dreams
The Sleep/ Dream/ Wake Cycle
Our Biological Clocks

Help Link : Sleeping and Waking Link : Researchers Show Mechanism And Similarities Of Biological Clocks Link : Biological Clock More Elegant than Believed
Link : Molecular and Genetic Analysis of the Mammalian Circadian Clock System Link : Glowing Cyanobacteria Gives Researchers New Clues To Circadian Rhythms Link : Mom May Set Your Body Clock, Suggests Science Research Link : Suprachiasmatic Nucleus Circadian Oscillatory Protein, a Novel Binding Partner of K-Ras in the Membrane Rafts, Negatively Regulates MAPK Pathway
Research : Biological Clockworks : 2000 Lecturers Research : Martin R. Ralph Research : Michael Rosbash, Ph.D. Research : Joseph S. Takahashi, Ph.D.
Resarch : Amita Sehgal Research : Lecture 2: Unwinding Clock Genetics Research : Lecture 4: The Mammalian Timekeeper
History : Biological Clocks: Museum
Original modules
Module Tool : Cybernetics Cybernetics
History Module: How Biological Clock Genes Were First Discovered in Fruit Flies   How Biological Clock Genes Were First Discovered in Fruit Flies

The protein casein kinase 1 epsilon (CSNK1E), which is the equivalent in mammals of the DOUBLE-TIME protein in the fruit fly, plays three different roles in the human biological clock. First, this protein phosphorylates the PER proteins produced in the cytoplasm, makes them less stable, and accelerates their degradation. Second, CSNK1E helps the PER/CRY and PER/PER complexes to penetrate the cell nucleus. And third, CSNK1E is found inside the nucleus, where it is involved in the degradation of the inhibitory complex formed by the PER/CRY and PER/PER complexes.

Link : Role of casein kinase 1 epsilon

This triple role makes it easier to understand why a mutation that affects just one amino acid in CSNK1E could significantly shorten the body’s circadian period. This is what happens with the tau mutation in golden hamsters–the first mutation discovered to affect the circadian period of a mammal. This discovery was made by U.S. neuroscientists Martin Ralph and Michael Menaker in 1988.

This mutation makes CSNK1E less effective in phosphorylating PER protein molecules, so they accumulate in the cytoplasm faster, enter the nucleus faster, and inhibit the per gene’s production of PER protein more quickly. Thus, the overall result is that hamsters with the tau mutation have shorter circadian cycles than normal hamsters.

Ralph and Menaker found that while hamsters that did not have the tau mutation had circadian cycles with a period of about 24 hours, hamsters that were heterozygous for this mutation (had it on only one of the two genes for CSNK1E) had circadian periods of about 22 hours, and hamsters that were homozygous for this mutation (had it on both of these genes) had circadian periods of about 20 hours.

Similar mutations in the CSNK1E genes also produce shorter circadian periods in humans. But recent studies seem to have revealed other mechanisms that are far more complex.

Lien : Tau-mutant hamsters Lien : Gene Mutation Upsets Mammalian Biological Clock Lien : Tau-mutant hamsters

The circadian rhythms (from the Latin circa dies, meaning “around a day”) that are observed both in plants and in animals are produced by a biological clock that operates in a negative feedback loop. This kind of loop is very common in biological organisms, but ones with such a long period as this–about 24 hours–are far rarer. Most feedback loops in living organisms have periods on the order of a minute, a second, or even a millisecond.

The various genes involved in this very special 24-hour loop were first isolated in the fruit fly, Drosophila, in the early 1970s (follow the History Module link to the left). In the late 1990s, the equivalent genes were isolated in mice and in humans. In addition, these genes were found to be expressed in the neurons of the suprachiasmatic nuclei of the hypothalamus, which was consistent with the role that these neurons were known to play in controlling the circadian rhythm.

At the molecular level, the role of each of the main components in the human biological clock can be described as follows (bear in mind that each of these components often has several sub-types with slightly different functions). The two mainsprings of this mechanism are the period (per) gene and the cryptochrome (cry) gene. These genes cannot be active unless two protein molecules, CLOCK and BMAL1, linked to each other to form a complex, bind to a specific site on the genes’ DNA sequences, known as the E-box element. When this complex binds to the E-box elements of the per and cry genes, it enables their DNA to be transcribed into messenger RNA (mRNA). Unlike the genes’ DNA, their mRNA can exit the nucleus through the nuclear pores and enter the cytoplasm, where it is translated into the proteins PER and CRY, respectively, by the cell’s ribosomes.

The protein PER degrades rapidly unless it too forms a complex. This complex may consist either of PER molecules (a PER/PER complex) or of PER molecules and CRY molecules (a PER/CRY complex). These two types of complexes then penetrate the cell’s nucleus, where they interact with the CLOCK/BMAL1 complexes so as to render them, and hence the per and cry genes, inactive. Thus the negative feedback loop is formed: by inhibiting these genes from which they originated, the PER and CRY proteins end up inhibiting their own production.

After a while, however, the PER/PER and PER/CRY complexes degrade and are replaced by other complexes that also have entered the nucleus. Eventually, precisely because the cell is no longer producing any PER or CRY molecules, there are no longer enough PER/PER and PER/CRY complexes left to block the activation of the per and cry genes. The inhibition on the CLOCK/BMAL1 complexes is thus released, and the transcription of per and cry mRNA resumes. At this point, about 24 hours have elapsed since this entire cycle began.

Source: Howard Hughes Medical Institute

The human biological clock is extremely regular: it is accurate to within 1%. But just like a watch that is never absolutely accurate on its own and needs to be reset occasionally, this biological clock needs a mechanism to prevent tiny errors from accumulating in each cell. In other words, it needs to synchronize itself with external signs that tell it when each new day begins. The growing intensity of the natural light is the first sign of daybreak, and special photopigments in the retina detect this change in light intensity and transmit this information to the human biological clock.

Certain proteins involved in the feedback loops in the human biological clock may also be involved in controlling the cycle of division in human cells. .

If some proteins in the biological clock are involved in the mechanisms of cell division, then they might also be involved in abnormalities in cellular cycles, such as the proliferation of cancerous tumours. In mice, for example, certain disorders of the SCN cause tumours to grow more quickly, and in humans, certain types of cancer are more common among people who work night shifts.

The variations in the efficacy of certain forms of chemotherapy according to the time of day that they are administered seem to confirm the close linkages between cellular cycles and the biological clock.

Link : HORLOGE BIOLOGIQUE :  la danse au rythme de l'ADN Link : L'horloge biologique rythme la vie des cellules

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