LSM12 is a Circadian Adaptor Important for ATAXIN­2­dependent Translation in Drosophila Clocks

Abstract

Mutations in human ATAXIN-2 (ATXN2/ATX2) have been implicated in neurodegenerative diseases such as spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis. Recent studies identified a RNA-binding protein complex of ATX2, TWENTY-FOUR (TYF), and polyA-binding protein that activates translation of a rate-limiting clock gene, PERIOD (PER), in Drosophila circadian clocks. Here we show that LSM12 is a novel component of the ATX2 co-activator complex important for clock function. Lsm12 mutant flies exhibit long-period behavioral rhythms with dampened PER cycling. LSM12 or PER overexpression rescues circadian defects in lsm12 mutants while lsm12 mutation sensitizes period-lengthening effects by TYF inhibition. Importantly, lack of LSM12 attenuates TYF loading onto ATX2 co-activator complex and suppresses the translational activation by RNA-tethered TYF. Taken together our data suggest that LSM12 is a circadian adaptor of the ATX2 co-activator complex to stimulate TYF-mediated PER translation, thus sustaining circadian behaviors with high-amplitude PER cycling. We propose an adaptor-specific targeting of the ATX2 co-activator complex might be responsible for Atx2 effects on discrete biological time-scales.