Alterations of per RNA in Noncoding Regions Affect Periodicity of Circadian Behavioral Rhythms

Abstract

Circadian rhythms in Drosophila depend on a molecular feedback loop that includes products of the period (per) and timeless (tim) genes. RNA and protein products of both genes cycle with a circadian period and the proteins feedback to inhibit expression of their own mRNAs. While cyclic expression of PER protein appears to be necessary for rhythmic behavior, the function of per RNA cycling is somewhat controversial. Rhythmic transcription accounts, in part, for cycling of per RNA, but it is clear now that posttranscriptional mechanisms also contribute to the cyclic expression of both per RNA and protein. As posttranscriptional mechanisms, such as mRNA stability and translation, are frequently mediated by 3' untranslated regions (UTR) of genes, the authors examined the role of this region of per in the regulation of circadian rhythms. Removal of most of per's 3' UTR had a small effect on the function of a per transgene. However, replacement of per's 3'UTR with corresponding sequences of the tubulin gene led to the rescue of behavioral rhythms in per01 flies with periods that were 3 h shorter than those generated by a wild-type per transgene. The hybrid RNA cycles, but the protein produced by it accumulates earlier in a day-night cycle than the PER protein produced by a control per transgene carrying its own 3'UTR, perhaps because the tubulin sequences counteract the effect of destabilizing elements in the per RNA at earlier points in the circadian cycle. These data indicate that the appropriate regulation of per RNA expression, effected by transcriptional as well as posttranscriptional mechanisms, is critical for the determination of circadian period.

Post-transcriptional control of circadian rhythms

“…A later study demonstrated that an element in the 3Ј-UTR of Per1 promotes its instability, thereby contributing to this destabilization (Kojima et al, 2003). The 3Ј-UTRs of other clock genes, such as Drosophila Per, rat Aanat, and mouse Per2, Per3 and Cry1, also contribute to regulating their rhythmic expression, thereby leading to an accurate circadian period (Chen et al, 1998;Kim et al, 2005;Kim et al, 2007a;Kwak et al, 2006;Woo et al, 2010;Woo et al, 2009).…”

Posttranscriptional Regulation of Mammalian Circadian Clock Output

“…(The same study also showed that posttranscriptional events are involved in the generation of the mRNA rhythm of a clock-controlled gene called Crg-1.) dPer mRNA contains elements in its 5´and 3´UTRs that affect PER protein cycling and fly behavior, probably through regulation of mRNA stability (Chen et al 1998;Stanewsky et al 2002). Additionally, it has been shown that translation is also under circadian regulation; two alternative splicing variants exhibit different translational properties, and cyclic dPer mRNA is not required for PER protein rhythmicity .…”

LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1

“…In Drosophila, dper mRNA half-life also appears to be regulated by the circadian clock, resulting in different message stability during accumulating and decay phases (20). Also, the circadian cycling of dPER levels depends on the 3Ј UTR of the dper mRNA (21).…”