Molecular mechanism of the Neurospora circadian oscillator

Abstract

Circadian clocks are the internal time-keeping mechanisms for organisms to synchronize their cellular and physiological processes to the daily light/dark cycles. The molecular mechanisms underlying circadian clocks are remarkably similar in eukaryotes. Neurospora crassa, a filamentous fungus, is one of the best understood model organisms for circadian research. In recent years, accumulating data have revealed complex regulation in the Neurospora circadian clock at transcriptional, posttranscriptional, post-translational and epigenetic levels. Here we review the recent progress towards our understanding of the molecular mechanism of the Neurospora circadian oscillator. These advances have provided novel insights and furthered our understanding of the mechanism of eukaryotic circadian clocks.

Circadian oscillator proteins across the kingdoms of life: structural aspects

“…The clockwork operates by the actions of positive and negative regulatory elements that form a complex network of multiple interlocked transcriptional and translational feedback loops that are self-sustained with robust and tunable molecular oscillators [3, 13, 14, 16, 17, 46, 47]. Recent work emphasizes the importance of post-translation regulation on the stability and functionality of clock components and, hence, circadian timing.…”

“…3b), WHITE COLLAR 1 (WC-1), WHITECOLLAR 2 (WC-2), FREQUENCY (FRQ), and FRQ-INTERACTING RNA HELICASE (FRH) form crucial components of the clock. WC-1 and WC-2 are GATA-type zinc-finger DNA binding transcription factors that form the positive elements of the rhythmic loop [2, 47]. Together, they form a heterodimeric WHITE COLLAR COMPLEX (WCC) via their PER-ARNT-SIM (PAS) domains that bind to two light-responsive elements (LREs) of the frq promoter and activate the transcription of frq .…”

“…The two isoforms form a dimeric complex that interacts with WCC and inhibits frq transcription [15]. WCC-FRQ interaction is mediated by FRH [47, 97]. FRQ is simultaneously and progressively phosphorylated to release the repression on D-WCC and is degraded via a ubiquitin-proteasome-mediated pathway.…”

“…The central and C-terminal part of FRQ is predicted to be largely unstructured and has no sequence similarity to any known protein domain [97, 104]. Apart from its role in the clock feedback loop, WC-1 is also a blue-light photoreceptor important for photomorphogenesis [2, 47, 96]. Light activation of WC-1 possibly results in the formation of a large WCC complex (L-WCC) that binds to the LREs, leading to the activation of transcription of the light-induced genes ( frq and vivid ( vvd ) are two of them) [2, 101, 105–107].…”

Posttranscriptional mechanisms in controlling eukaryotic circadian rhythms

“…In addition to these central elements, many other components are also crucial for clock function, including kinases, phosphatases, and deacetylases, which modify essential protein components of the clock at multiple levels. The function of all of these circuits is to maintain robust circadian rhythms [17–21].…”