![]() ![]() ![]() Now, cryptochrome (CRY) is a light sensitive protein which inhibits TIM in the presence of light. Therefore, inhibition of CLK/CYC lowers per and tim mRNA levels, which in turn lower the levels of PER and TIM. This CLOCK/CYCLE complex acts as a transcriptional activator for per and tim by binding to specific enhancers (called E-boxes) of their promoters. After PER is produced from per mRNA, it dimerizes with Timeless (TIM) and the complex goes into the nucleus and inhibits the transcription factors of per and tim, the CLOCK/CYCLE heterodimer. However, because PER protein cannot directly bind to DNA, it does not directly influence its own transcription alternatively, it inhibits its own activators. When PER levels increase, the inhibition of per transcription increases, lowering the protein levels. The per product PER also oscillates with a nearly 24 hour period, peaking about six hours after per mRNA levels during the middle subjective night. In Drosophila, per mRNA levels oscillate with a period of approximately 24 hours, peaking during the early subjective night. In 1998, it was discovered that per produces two transcripts (differing only by the alternative splicing of a single untranslated intron) which both encode the PER protein. The period gene was first sequenced in 1984 by Michael Rosbash and colleagues. The discovery of mutants that altered the period of circadian rhythms in eclosion and locomotor activity ( per S and per L) indicated the role of the per gene in the clock itself and not an output pathway. The per S, per L, and per 0 mutations were found to complement each other, so it was concluded that the three phenotypes were due to mutations in the same gene. The period gene and three mutants ( per S, per L, and per 0) were isolated in an EMS mutagenesis screen by Ronald Konopka and Seymour Benzer in 1971. ![]()
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