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First published online 5 March 2008
doi: 10.1242/dev.016295

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APC/C^Fzr/Cdh1 promotes cell cycle progression during the Drosophila endocycle

Karine Narbonne-Reveau¹, Stefania Senger¹, Margit Pal², Anabel Herr^3,*, Helena E. Richardson³, Maki Asano⁴, Peter Deak² and Mary A. Lilly^1,

¹ Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
² Institute of Biochemistry, Biological Research Center, Temesvari krt. 62, H-6726, Szeged, Hungary.
³ Cell Cycle and Development Lab, Peter MacCallum Cancer Center, 7 St Andrews place, East Melbourne, 3002 Victoria, Australia.
⁴ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Author for correspondence (e-mail: mlilly{at}helix.nih.gov)

Accepted 21 February 2008

The endocycle is a commonly observed variant cell cycle in which cells undergo repeated rounds of DNA replication with no intervening mitosis. How the cell cycle machinery is modified to transform a mitotic cycle into endocycle has long been a matter of interest. In both plants and animals, the transition from the mitotic cycle to the endocycle requires Fzr/Cdh1, a positive regulator of the Anaphase-Promoting Complex/Cyclosome (APC/C). However, because many of its targets are transcriptionally downregulated upon entry into the endocycle, it remains unclear whether the APC/C functions beyond the mitotic/endocycle boundary. Here, we report that APC/C^Fzr/Cdh1 activity is required to promote the G/S oscillation of the Drosophila endocycle. We demonstrate that compromising APC/C activity, after cells have entered the endocycle, inhibits DNA replication and results in the accumulation of multiple APC/C targets, including the mitotic cyclins and Geminin. Notably, our data suggest that the activity of APC/C^Fzr/Cdh1 during the endocycle is not continuous but is cyclic, as demonstrated by the APC/C-dependent oscillation of the pre-replication complex component Orc1. Taken together, our data suggest a model in which the cyclic activity of APC/C^Fzr/Cdh1 during the Drosophila endocycle is driven by the periodic inhibition of Fzr/Cdh1 by Cyclin E/Cdk2. We propose that, as is observed in mitotic cycles, during endocycles, APC/C^Fzr/Cdh1 functions to reduce the levels of the mitotic cyclins and Geminin in order to facilitate the relicensing of DNA replication origins and cell cycle progression.

Key words: APC/C, Cdh1, Cyclin E, Drosophila, endoreplication, endocycle, Fzr/Cdh1, Geminin

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