Modeling the control of DNA replication in fission yeast

Modeling the control of DNA replication in fission yeast

Bela Novak* and
John J. Tyson†

^*Department of Agricultural Chemical Technology, Technical University of Budapest, 1521 Budapest, St. Gellert ter 4, Hungary; and ^†Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061

Edited by Paul Nurse, Imperial Cancer Research Fund, London, United Kingdom, and approved May 21, 1997 (received for review December 31, 1996)

Abstract

A central event in the eukaryotic cell cycle is the decision to commence DNA replication (S phase). Strict controls normally operate to prevent repeated rounds of DNA replication without intervening mitoses (“endoreplication”) or initiation of mitosis before DNA is fully replicated (“mitotic catastrophe”). Some of the genetic interactions involved in these controls have recently been identified in yeast. From this evidence we propose a molecular mechanism of “Start” control in Schizosaccharomyces pombe. Using established principles of biochemical kinetics, we compare the properties of this model in detail with the observed behavior of various mutant strains of fission yeast: wee1 ⁻ (size control at Start), cdc13Δ and rum1 ^OP (endoreplication), and wee1 ⁻ rum1Δ (rapid division cycles of diminishing cell size). We discuss essential features of the mechanism that are responsible for characteristic properties of Start control in fission yeast, to expose our proposal to crucial experimental tests.

Footnotes

This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: SPF, S-phase promoting factor; MPF, M-phase promoting factor; CDK, cyclin-dependent kinase; UbE, ubiquitin-ligating enzyme; DE, differential equation.
↵ ‡ Cig2 level is high in cells blocked in S phase with hydroxyurea (20), when Rum1 is absent, so the controls must be more complex. Perhaps degradation of Cig2 cannot occur until S phase is completed.
↵ § We use boldface to distinguish the G₁ steady state of the control system (a stable, time-invariant state with low CDK activity) from the traditional G₁ phase of the cell cycle (when the genome is unreplicated). The G₁ steady state represents the physiologist’s notion of a checkpoint in G₁ phase: a state where cells arrest until they are ready to initiate a new round of DNA synthesis. Similarly, the G₂ steady state represents a checkpoint in G₂ phase, before entering mitosis. “Surveillance mechanisms” maintain stability of the G₁ (G₂) steady state as long as necessary preparations for S phase (M phase) are not yet completed. In this model of fission yeast, cell growth is the only preparation necessary for starting DNA synthesis.