A Timeless debate: resolving TIM's noncircadian roles with possible clock function.

Mammalian TIMELESS (TIM) was identified due to its sequence similarity to Drosophila TIM, an essential circadian clock protein in flies. Published literature is inconsistent regarding the rhythmic expression of mammalian Tim, the interaction of the TIM protein with other clock proteins and its role in regulating clock gene transcription. Comprehensive sequence analysis not only demonstrates that mammalian TIM is more similar to a second, TIM-like sequence in Drosophila (TIMEOUT), but is also a member of an evolutionarily conserved family of TIM orthologs that is distinct from the circadian-specific TIM proteins found in insects. The vital cellular function of these widely conserved TIM orthologs makes it difficult to determine the specific role of mammalian TIM in the circadian clock mechanism.