Biological clock

A biological clock is a physiological mechanism which regulates the timing of any biological process or activity. The biological clock is not a single cell, neuron or collection of neural cells. Neither is it a result of activity of a single gene. Instead, several mechanisms have been identified in various animal groups. Often the biological clock refers to a cellular oscillator in vertebrates, residing mostly in the suprachiasmatic nucleus of the hypothalamus (in mammals), controlling the diurnal (or day-night) cycle of animal activity, wakefulness, hormonal cycles etc. Other, long-term neural oscillators control the reproductive cycle, whose length varies a lot between species. Most biological clocks are regulated by light in some manner, either by means of phase locking to the light-dark cycle (as in the diurnal oscillator) or some other regular change (seasonal, lunar). Otherwise, i.e. colloquially, a biological clock generally refers to the onset of menopause and associated loss of reproductive capabilities in female humans.

The clock genes

The suprachiasmatic nucleus, which lies directly above the optic chiasm at the base of the hypothalamus receives a strong direct neural input from the retina, and is the key site for the control of biological rhythms that are entrained by light. In the suprachiasmatic nucleus, rhythms of neuronal activity with a period of about 24 hours (circadian rhythms) are formed by dynamic cycles of transcription and translation of clock genes. The clock genes regulate a self-sustaining rhythm in cells so that, even without light, they will maintain a roughly 24 hour rhythm. An extreme example is of cave fish which have lived in complete darkness for millions of years and their clock genes are still present in their DNA.

The rhythmic output of organs can be influenced by metabolic, endocrine and homeostatic events, as well as by the circadian clock. For example, the SCN can change the rhythm of expression of liver genes and enzymes without using clock genes, but through second messenger systems induced by the autonomic nervous system instead. Other genes can also affect circadian clock genes; for example the ROR-alpha gene is a positive regulator of Bmal1, which regulates lipogenesis and lipid storage.

Genes which encode important proteins of core clock mechanism are Clock (circadian locomotor output cycles kaput); Bmal1 (brain and muscle-Arnt-like 1); the Period genes Per1, Per2 and Per3); and the Cryptochrome genes Cry1 and Cry2. CLOCK (the protein product of Clock) is a transcription factor which dimerises with BMAL1 (the protein product of Bmal1). CLOCK and BMAL1 form a complex which binds to E-box, a DNA sequence in the promoter region of the gene, and to other similar promoter sequences. The binding of the CLOCK:BMAL1 complex to the E-box in the promoter region of ""Per"" and ""Cry"" activates their transcription. In turn, the PER and CRY proteins are able to undergo nuclear transformation and inhibit the CLOCK:BMAL1 complex, resulting in the decreased transcription of their owm genes. CLOCK:BMAL1 and PER-CRY transcription-translation loop is able to detect and self adjust to the changes. CLOCK:BMAL1 and PER-CRY constitute the core of the circadian clock and, because of the delays in transcription and translation, can generate 24-hour rhythms of gene expression.