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Mol Cell. 2014 May 22;54(4):651-62. doi: 10.1016/j.molcel.2014.04.015. Epub 2014 May 15.

Rhythmic U2af26 alternative splicing controls PERIOD1 stability and the circadian clock in mice.

Author information

1
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
2
Institut de Recherches Cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
3
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany. Electronic address: florian.heyd@fu-berlin.de.

Abstract

The circadian clock drives daily rhythms in gene expression to control metabolism, behavior, and physiology; while the underlying transcriptional feedback loops are well defined, the impact of alternative splicing on circadian biology remains poorly understood. Here we describe a robust circadian and light-inducible splicing switch that changes the reading frame of the mouse mRNA encoding U2-auxiliary-factor 26 (U2AF26). This results in translation far into the 3' UTR, generating a C terminus with homology to the Drosophila clock regulator TIMELESS. This new U2AF26 variant destabilizes PERIOD1 protein, and U2AF26-deficient mice show nearly arrhythmic PERIOD1 protein levels and broad defects in circadian mRNA expression in peripheral clocks. At the behavioral level, these mice display increased phase advance adaptation following experimental jet lag. These data suggest light-induced U2af26 alternative splicing to be a buffering mechanism that limits PERIOD1 induction, thus stabilizing the circadian clock against abnormal changes in light:dark conditions.

PMID:
24837677
DOI:
10.1016/j.molcel.2014.04.015
[Indexed for MEDLINE]
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