Evaluating putative mechanisms of the mitotic spindle checkpoint

doi:10.1073/pnas.0409142102

Evaluating putative mechanisms of the mitotic spindle checkpoint

Departments of ^†Molecular Genetics and ^∥Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel; ^‡Department of Biomedical Engineering, The Iby and Aladar Fleischman Faculty of Engineering, and ^§School of Physics and Astronomy, Beverly and Raymond Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel; and ^¶Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093-0319

Edited by Michael Levitt, Stanford University School of Medicine, Stanford, CA, and approved March 17, 2005 (received for review December 8, 2004)

Abstract

The mitotic spindle checkpoint halts the cell cycle until all chromosomes are attached to the mitotic spindles. Evidence suggests that the checkpoint prevents cell-cycle progression by inhibiting the activity of the APC-Cdc20 complex, but the precise mechanism underlying this inhibition is not yet known. Here, we use mathematical modeling to compare several mechanisms that could account for this inhibition. We describe the interplay between the capacities to strongly inhibit cell-cycle progression before spindle attachment on one hand and to rapidly resume cell-cycle progression once the last kinetochore is attached on the other hand. We find that inhibition that is restricted to the kinetochore region is not sufficient for supporting both requirements when realistic diffusion constants are considered. A mechanism that amplifies the checkpoint signal through autocatalyzed inhibition is also insufficient. In contrast, amplifying the signal through the release of a diffusible inhibitory complex can support reliable checkpoint function. Our results suggest that the design of the spindle checkpoint network is limited by physical constraints imposed by realistic diffusion constants and the relevant spatial and temporal dimensions where computation is performed.

Footnotes

↵ †† To whom correspondence should be sent at the † address. E-mail: naama.barkai{at}weizmann.ac.il.
This paper was submitted directly (Track II) to the PNAS office.