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Molecular and Cellular Biology, March 2002, p. 1868-1880, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1868-1880.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Control of DNA Replication and Chromosome Ploidy by Geminin and Cyclin A

Ivailo S. Mihaylov,1 Takeshi Kondo,1 Lynn Jones,1 Sophia Ryzhikov,1 Junko Tanaka,2 Jianyu Zheng,1 Leigh Ann Higa,1 Naoto Minamino,2 Lynn Cooley,1 and Hui Zhang1*

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520 ,1 National Cardiovascular Center Research Institute, Suita, 565-8565 Osaka, Japan2

Received 17 July 2001/ Returned for modification 26 November 2001/ Accepted 10 December 2001

Alteration of the control of DNA replication and mitosis is considered to be a major cause of genome instability. To investigate the mechanism that controls DNA replication and genome stability, we used the RNA silencing-interference technique (RNAi) to eliminate the Drosophila geminin homologue from Schneider D2 (SD2) cells. Silencing of geminin by RNAi in SD2 cells leads to the cessation of mitosis and asynchronous overreplication of the genome, with cells containing single giant nuclei and partial ploidy between 4N and 8N DNA content. The effect of geminin deficiency is completely suppressed by cosilencing of Double parked (Dup), the Drosophila homologue of Cdt1, a replication factor to which geminin binds. The geminin deficiency-induced phenotype is also partially suppressed by coablation of Chk1/Grapes, indicating the involvement of Chk1/Grapes in the checkpoint control in response to overreplication. We found that the silencing of cyclin A, but not of cyclin B, also promotes the formation of a giant nucleus and overreplication. However, in contrast to the effect of geminin knockout, cyclin A deficiency leads to the complete duplication of the genome from 4N to 8N. We observed that the silencing of geminin causes rapid downregulation of Cdt1/Dup, which may contribute to the observed partial overreplication in geminin-deficient cells. Analysis of cyclin A and geminin double knockout suggests that the effect of cyclin A deficiency is dominant over that of geminin deficiency for cell cycle arrest and overreplication. Together, our studies indicate that both cyclin A and geminin are required for the suppression of overreplication and for genome stability in Drosophila cells.

* Corresponding author. Mailing address: Department of Genetics, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Phone: (203) 737-1922. Fax: (203) 785-7023. E-mail: hui.zhang{at}yale.edu.

Molecular and Cellular Biology, March 2002, p. 1868-1880, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1868-1880.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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