TIMELESS-dependent positive and negative autoregulation in the Drosophila circadian clock

EMBO J. 1999 Feb 1;18(3):675-86. doi: 10.1093/emboj/18.3.675.

Abstract

The timeless protein (TIM) is a central component of the circadian pacemaker machinery of the fruitfly Drosophila melanogaster. Both TIM and its partner protein, the period protein PER, show robust circadian oscillations in mRNA and protein levels. Yet the role of TIM in the rhythm generation mechanism is largely unknown. To analyze TIM function, we constructed transgenic flies that carry a heat shock-inducible copy of the timeless gene (tim) in an arrhythmic tim loss-of-function genetic background. When heat shocked, TIM levels in these flies rapidly increased and initiated a molecular cycle of PER accumulation and processing with dynamics very similar to the PER cycle observed in wild-type flies. Analysis of period (per) mRNA levels and transcription uncovered a novel role for TIM in clock regulation: TIM increases per mRNA levels through a post-transcriptional mechanism. Our results suggest positive as well as negative autoregulation in the Drosophila circadian clock.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Animals, Genetically Modified
  • Basic Helix-Loop-Helix Transcription Factors
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • Dimerization
  • Drosophila Proteins*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology*
  • Gene Expression
  • Genes, Insect
  • Homeostasis
  • Hot Temperature
  • Insect Proteins / chemistry
  • Insect Proteins / genetics
  • Insect Proteins / physiology*
  • Models, Biological
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Period Circadian Proteins
  • Phosphorylation
  • Protein Conformation
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcription, Genetic

Substances

  • ARNTL Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • Drosophila Proteins
  • Insect Proteins
  • Nuclear Proteins
  • PER protein, Drosophila
  • Period Circadian Proteins
  • RNA, Messenger
  • Trans-Activators
  • cyc protein, Drosophila
  • tim protein, Drosophila