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The Journal of Neuroscience, January 28, 2009, 29(4):1152-1162; doi:10.1523/JNEUROSCI.0429-08.2009

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Cellular/Molecular
The COP9 Signalosome Is Required for Light-Dependent Timeless Degradation and Drosophila Clock Resetting

Alyson Knowles,¹ Kyunghee Koh,² June-Tai Wu,³ Cheng-Ting Chien,³ Daniel A. Chamovitz,⁴ and Justin Blau¹

¹Department of Biology, New York University, New York, New York 10003, ²Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, ³Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan, and ⁴Department of Plant Sciences, Tel Aviv University, Tel Aviv 69978, Israel

Correspondence should be addressed to Justin Blau, Department of Biology, New York University, 100 Washington Square East, New York, NY 10003. Email: justin.blau{at}nyu.edu

The ubiquitin–proteasome system plays a major role in the rhythmic accumulation and turnover of molecular clock components. In turn, these 24 h molecular rhythms drive circadian rhythms of behavior and physiology. In Drosophila, the ubiquitin–proteasome system also plays a critical role in light-dependent degradation of the clock protein Timeless (TIM), a key step in the entrainment of the molecular clocks to light–dark cycles. Here, we investigated the role of the COP9 signalosome (CSN), a general regulator of protein degradation, in fly circadian rhythms. We found that null mutations in the genes encoding the CSN4 and CSN5 subunits prevent normal TIM degradation by light in the pacemaker lateral neurons (LNs) as does LN-specific expression of a dominant-negative CSN5 transgene. These defects are accompanied by strong reductions in behavioral phase shifts of adult flies lacking normal CSN5 activity in LNs. Defects in TIM degradation and resetting of behavioral phases were rescued by overexpression of Jetlag (JET), the F-box protein required for light-mediated TIM degradation. Flies lacking normal CSN activity in all clock neurons are rhythmic in constant light, a phenotype previously associated with jet mutants. Together, these data indicate that JET and the CSN lie in a common pathway leading to light-dependent TIM degradation. Surprisingly, we found that manipulations that strongly inhibit CSN activity had minimal effects on circadian rhythms in constant darkness, indicating a specific role for the CSN in light-mediated TIM degradation.

Key words: circadian rhythms; COP9 signalosome; Timeless; protein degradation; light signaling; entrainment

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Received Jan. 30, 2008; revised Dec. 19, 2008; accepted Dec. 22, 2008.

Correspondence should be addressed to Justin Blau, Department of Biology, New York University, 100 Washington Square East, New York, NY 10003. Email: justin.blau{at}nyu.edu

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