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J. Biol. Chem., Vol. 280, Issue 20, 19689-19694, May 20, 2005

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Caenorhabditis elegans Geminin Homologue Participates in Cell Cycle Regulation and Germ Line Development^*

Ken-ichiro Yanagi, Takeshi Mizuno, Takashi Tsuyama¶, Shusuke Tada¶, Yumi Iida||, Asako Sugimoto||, Toshihiko Eki**, Takemi Enomoto¶, and Fumio Hanaoka

From the Cellular Physiology Laboratory, Discovery Research Institute, RIKEN, CREST, Japan Science and Technology Corporation, Wako, Saitama 351-0198, the ^¶Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, the ^||Laboratory for Developmental Genomics, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, the ^**Department of Ecological Engineering, Toyohashi University of Technology, Toyohashi, Aichi 441-8580, and the Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan

Cdt1 is an essential component for the assembly of a pre-replicative complex. Cdt1 activity is inhibited by geminin, which also participates in neural development and embryonic differentiation in many eukaryotes. Although Cdt1 homologues have been identified in organisms ranging from yeast to human, geminin homologues had not been described for Caenorhabditis elegans and fungi. Here, we identify the C. elegans geminin, GMN-1. Biochemical analysis reveals that GMN-1 associates with C. elegans CDT-1, the Hox protein NOB-1, and the Six protein CEH-32. GMN-1 inhibits not only the interaction between mouse Cdt1 and Mcm6 but also licensing activity in Xenopus egg extracts. RNA interference-mediated reduction of GMN-1 is associated with enlarged germ nuclei with aberrant nucleolar morphology, severely impaired gametogenesis, and chromosome bridging in intestinal cells. We conclude that the Cdt1-geminin system is conserved throughout metazoans and that geminin has evolved in these taxa to regulate proliferation and differentiation by directly interacting with Cdt1 and homeobox proteins.

Received for publication, February 22, 2005 , and in revised form, March 25, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB190260.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and grants from the Bioarchitect Research Project and the Chemical Biology Project of RIKEN. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-7975; Fax: 81-6-6877-9382; E-mail: fhanaoka{at}fbs.osaka-u.ac.jp.

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