Quantitative Biology Colloquium

A mathematical model for the mammalian cell cycle is developed that considers the cycle as a sequence of tasks that must be successfully completed in order.  Each task is the result of a relatively long process (“integrate”) whose completion triggers a relatively rapid response (“fire”).  The model contrasts with previous ones in several ways.  It is autonomous, with the cycle driven by growth factors and not any externally imposed “growth” clock.  It accounts for the fact that cell cycle progression is not merely driven by cascading waves of cell cycle controllers, but rather must of necessity be coupled to the successful completion of essential tasks.  The tasks considered are the most essential ones for the cell cycle: passage of the restriction point, licensing of origins, firing of origins and completion of DNA replication, nuclear envelope breakdown, kinetochore attachment, passage of the spindle checkpoint, and mitosis.  Primary cell cycle controllers considered are Cyclin D1 (in complex with CDK4/6), APCCdh1, CDC25A, SCF, RPA, MPF, and APCCdc20.  While there is no shortage of prime candidates for “master regulators” of the cell cycle, the selections made here were dictated by the need to relate cell cycle tasks to integrate-and-fire processes, and the necessity for mechanisms to detect successful completion of tasks. Biologists have not reached a consensus regarding certain key aspects of cell cycle control, and some of these issues are considered from the mathematical modeling perspective.  Does licensing of origins occur in M or in G1?  Is absence of Cdt1 in S phase truly the primary mechanism of preventing relicensing and rereplication in mammalian cells? If not, what is the primary mechanism, and could it be related to nuclear envelope breakdown?  How is the firing of origins regulated during S phase?  Could it be regulated by the same mechanism used for arresting S phase in the case of DNA damage?  Does the primary regulator triggering entry into S phase, CDC25A, peak at the G1-S transition, or does it continue to rise until M?  Generally, how does the cell cycle prevent tasks from occurring at the wrong time, and does it make sense to assume that the main mechanism is “absence” (near-zero levels) of certain cell cycle controllers?  We discuss how the biological literature provides conflicting answers to these questions, but how certain answers seem far more reasonable in the context of a mathematical model.