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Molecular and Cellular Biology, August 2001, p. 5156-5168, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5156-5168.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Loss of Cell Cycle Checkpoint Control in Drosophila Rfc4 Mutants

Sue A. Krause,1,dagger Marie-Louise Loupart,1 Sharron Vass,1 Stefan Schoenfelder,1,Dagger Steve Harrison,2 and Margarete M. S. Heck1,*

Wellcome Trust Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom,1 and Chiron Corporation, Emeryville, California 94608-29162

Received 10 November 2000/Returned for modification 7 December 2000/Accepted 26 April 2001

Two alleles of the Drosophila melanogaster Rfc4 (DmRfc4) gene, which encodes subunit 4 of the replication factor C (RFC) complex, cause striking defects in mitotic chromosome cohesion and condensation. These mutations produce larval phenotypes consistent with a role in DNA replication but also result in mitotic chromosomal defects appearing either as premature chromosome condensation-like or precocious sister chromatid separation figures. Though the DmRFC4 protein localizes to all replicating nuclei, it is dispersed from chromatin in mitosis. Thus the mitotic defects appear not to be the result of a direct role for RFC4 in chromosome structure. We also show that the mitotic defects in these two DmRfc4 alleles are the result of aberrant checkpoint control in response to DNA replication inhibition or damage to chromosomes. Not all surveillance function is compromised in these mutants, as the kinetochore attachment checkpoint is operative. Intriguingly, metaphase delay is frequently observed with the more severe of the two alleles, indicating that subsequent chromosome segregation may be inhibited. This is the first demonstration that subunit 4 of RFC functions in checkpoint control in any organism, and our findings additionally emphasize the conserved nature of RFC's involvement in checkpoint control in multicellular eukaryotes.

* Corresponding author. Mailing address: University of Edinburgh, Institute of Cell and Molecular Biology, Wellcome Trust Centre for Cell Biology, Michael Swann Building, King's Buildings, Mayfield Rd., Edinburgh EH9 3JR, United Kingdom. Phone: 44 (0) 131 650 7114. Fax: 44 (0) 131 650 7778. E-mail: margarete.heck{at}ed.ac.uk.

dagger Present address: University of Glasgow, Institute of Biological and Life Sciences, Division of Molecular Genetics, Glasgow G11 6NU, United Kingdom.

Dagger Present address: Zentrum fur Molekulare Biologie, Universitat Heidelberg, Heidelberg 69120, Germany.

Molecular and Cellular Biology, August 2001, p. 5156-5168, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5156-5168.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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