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S-phase checkpoint controls mitosis via an APC-independent Cdc20p function

Nature Cell Biology volume 5, pages 928–935 (2003)Cite this article

Abstract

Cells divide with remarkable fidelity, allowing complex organisms to develop and possess longevity. Checkpoint controls contribute by ensuring that genome duplication and segregation occur without error so that genomic instability, associated with developmental abnormalities and a hallmark of most human cancers1,2,3,4,5, is avoided. S-phase checkpoints prevent cell division while DNA is replicating6,7,8. Budding yeast Mec1p and Rad53p, homologues of human checkpoint kinases ATM/ATR and Chk2, are needed for this control system. How Mec1p and Rad53p prevent mitosis in S phase is not known. Here we provide evidence that budding yeasts avoid mitosis during S phase by regulating the anaphase-promoting complex (APC) specificity factor Cdc20p: Mec1p and Rad53p repress the accumulation of Cdc20p in S phase. Because precocious Cdc20p accumulation causes anaphase onset and aneuploidy, Cdc20p concentrations must be precisely regulated during each and every cell cycle. Catastrophic mitosis induced by Cdc20p in S phase occurs even in the absence of core APC components. Thus, Cdc20p can function independently of the APC.

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Figure 1: Cdc20p is necessary for and promotes spindle elongation during S phase.
Figure 2: Cdc20p accumulates prematurely in rad53-1 and mec1-1 cells.
Figure 3: Premature mitosis in an unperturbed cell cycle.
Figure 4: Spindle elongation in S phase is independent of APC function.
Figure 5: Model for organization of the S-phase checkpoint pathway.

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Acknowledgements

We are grateful to Steve Haase, Lehland Johnston, Jim Hwang and Peter Kaiser for providing strains and plasmids. DJC was supported by US Army DOD Breast Cancer Research Grant BRCP-97-1-7059, SJ by the Danish Medical Research Council. This work was supported in part by NIH grant 1R01CA85487-02 (SIR), Basil O'Connor March of Dimes Starter Scholarship 5-FY02-248 (DJC) and NCI grant 1R01CA99033-01 (DJC).

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Author notes

  1. Marisa Segal

    Present address: Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK

  2. Sanne Jensen

    Present address: Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, 2100, Copenhagen, Denmark

Authors and Affiliations

  1. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Duncan J. Clarke, Marisa Segal, Stanislav G. Rudyak, Sanne Jensen & Steven I. Reed

  2. Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, 420 Washington Avenue SE, Minneapolis, 55455, Minnesota, USA

    Duncan J. Clarke, Catherine A. Andrews & Karen Smith

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Correspondence to Steven I. Reed.

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Clarke, D., Segal, M., Andrews, C. et al. S-phase checkpoint controls mitosis via an APC-independent Cdc20p function. Nat Cell Biol 5, 928–935 (2003). https://doi.org/10.1038/ncb1046

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