MCB Accepts, published online ahead of print on 26 October 2009

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Mol. Cell. Biol. doi:10.1128/MCB.01154-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Circadian amplitude of cryptochrome 1 is modulated by mRNA stability regulation via cytoplasmic hnRNP D oscillation

Kyung-Chul Woo, Dae-Cheong Ha, Kyung-Ha Lee, Do-Yeon Kim, Tae-Don Kim, and Kyong-Tai Kim^*

Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, 790784, South Korea; Department of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, 790784, South Korea; Center for Stem Cell Research, Korea Research Institute of Bioscience and Biotechnology, 111, Gwahangno, Yuseong-gu, Daejeon, 305806, South Korea

^* To whom correspondence should be addressed. Email: ktk{at}postech.ac.kr.

The mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Its conserved molecular basis has been thought to consist of intracellular transcriptional feedback loops of key clock genes. However, little is known about post-transcriptional regulation of these genes. In the present study, we investigated the role of the 3'-untranslated region of the mouse cryptochrome 1 (mcry1) gene at the post-transcriptional level. Mature mcry1 mRNA has a 610-nucleotide 3'UTR, and mediates its own degradation. The middle part of the 3'UTR contains a destabilizing cis-acting element. The deletion of this element led to a dramatic increase in mRNA stability, and heterogeneous nuclear ribonucleoprotein (hnRNP) D was identified as an RNA-binding protein responsible for this effect. Cytoplasmic hnRNP D levels displayed a reciprocal pattern compared to mcry1 oscillation. Knockdown of hnRNP D stabilized mcry1 mRNA and resulted in enhancement of the oscillation amplitude and slight delay of the phase. Our results suggest that hnRNP D plays a role as a fine regulator, contributing to the mcry1 mRNA turnover rate and the modulation of circadian rhythm.