ATAXIN-2 Activates PERIOD Translation to Sustain Circadian Rhythms in Drosophila

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Science  17 May 2013:
Vol. 340, Issue 6134, pp. 875-879
DOI: 10.1126/science.1234785

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Although core components of circadian clocks in flies and mammals are transcriptional circuits, recent evidence indicates posttranscriptional regulation of the clock occurs. Studies from Lim and Allada (p. 875) and Zhang et al. (p. 879) converge to show that the protein ATAXIN-2, associated with neurodegenerative diseases in humans, is a regulator of translation required for normal clock function in pacemaker neurons and for daily rhythms of behavior. ATAXIN is an RNA-binding protein and cooperates in the accumulation of the Per (Period) protein, a core transcriptional regulatory component of the clock.


Evidence for transcriptional feedback in circadian timekeeping is abundant, yet little is known about the mechanisms underlying translational control. We found that ATAXIN-2 (ATX2), an RNA-associated protein involved in neurodegenerative disease, is a translational activator of the rate-limiting clock component PERIOD (PER) in Drosophila. ATX2 specifically interacted with TWENTY-FOUR (TYF), an activator of PER translation. RNA interference–mediated depletion of Atx2 or the expression of a mutant ATX2 protein that does not associate with polyadenylate-binding protein (PABP) suppressed behavioral rhythms and decreased abundance of PER. Although ATX2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered TYF and disrupted the association between TYF and PABP. Thus, ATX2 coordinates an active translation complex important for PER expression and circadian rhythms.

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