FRQ-Interacting RNA Helicase Mediates Negative and Positive Feedback in the Neurospora Circadian Clock

Dec 2, 2009Genetics

RNA helicase controls both negative and positive feedback in the Neurospora biological clock

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Abstract

A novel allele of the FRQ-interacting RNA helicase gene, frh(R806H), leads to complete disruption of circadian clock function.

The frh(R806H) allele results in an arrhythmic strain while maintaining essential viability functions of FRH.
FRH(R806H) interacts with FRQ, but the interaction with the White Collar Complex (WCC) is significantly impaired.
Reduced phosphorylation of WC-1 in the mutant leads to persistently elevated WCC activity, disrupting the negative feedback loop.
WCC levels, particularly those of WC-1, are considerably decreased, indicating a loss of positive feedback and reduced FRQ-mediated WCC stabilization.
Overexpression of FRH increases WC-1 levels, highlighting FRH's role in stabilizing WC-1 alongside FRQ.
The findings suggest that FRH has clock-specific functions that differ from its expected role in exosome-related processes.

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The Neurospora circadian oscillator comprises FREQUENCY (FRQ) and its transcription activator, the White Collar Complex (WCC). Repression of WCC's transcriptional activity by FRQ via negative feedback is indispensable for clock function. An unbiased genetic screen that targeted mutants with defects in negative feedback regulation yielded a fully viable arrhythmic strain bearing a novel allele of FRQ-interacting RNA helicase (frh), an essential gene that encodes a putative exosome component protein. In the allele, frh(R806H), clock function is completely disturbed, while roles of FRQ-interacting RNA helicase (FRH) essential for viability are left intact. FRH(R806H) still interacts with FRQ, but interaction between the FRQ-FRH(R806H) complex (FFC) and WCC is severely affected. Phosphorylation of WC-1 is reduced in the mutant leading to constantly elevated WCC activity, which breaks the negative feedback loop. WCC levels are considerably reduced in the mutant, especially those of WC-1, consistent both with loss of positive feedback (FRQ-dependent WC-1 stabilization) and with a reduced level of the FRQ-mediated WCC phosphorylation that leads to high WCC activity accompanied by rapid transcription-associated turnover. FRH overexpression promotes WC-1 accumulation, confirming that FRH together with FRQ plays a role in WC-1 stabilization. Identification of a viable allele of frh, displaying virtually complete loss of both negative and positive circadian feedback, positions FRH as a core component of the central oscillator that is permissive for rhythmicity but appears not to modulate periodicity. Moreover, the results suggest that there are clock-specific roles for FRH that are distinct from the predicted essential exosome-associated functions for the protein.

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FRQ-Interacting RNA Helicase Mediates Negative and Positive Feedback in the Neurospora Circadian Clock

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