title: Active transport can greatly enhance Cdc20:Mad2 formation.
abstract: To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis.The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint may lead to aneuploidy and likely contributes to the development of cancer. Kinetochores of unattached or misaligned chromosomes are thought to generate a diffusible ''wait-anaphase'' signal, which is the basis for downstream events to inhibit the anaphase promoting complex/cyclosome (APC/C). The rate of Cdc20:C-Mad2 complex formation at the kinetochore is a key regulatory factor in the context of APC/C inhibition. Computer simulations of a quantitative SAC model show that the formation of Cdc20:C-Mad2 is too slow for checkpoint maintenance when cytosolic O-Mad2 has to encounter kinetochores by diffusion alone. Here, we show that an active transport of O-Mad2 towards the spindle mid-zone increases the efficiency of Mad2-activation. Our data indicate that this mechanism can greatly enhance the formation of Cdc20:Mad2 and furthermore gives an explanation on how the ''wait-anaphase'' signal can dissolve abruptly within a short time. Our results help to understand parts of the SAC mechanism that remain unclear.
authors.affiliation: Al-Qunfudah University College, Umm Al-Qura University, 1109 Makkah Al-Mukarramah, Saudi Arabia. bashar.ibrahim@uni-jena.de.
authors.forename: Bashar
authors.initials: B
authors.lastname: Ibrahim
authors.affiliation: Bio Systems Analysis Group, Institute of Computer Science, Jena Center for Bioinformatics and Friedrich Schiller University, 07743 Jena, Germany. richard.henze@uni-jena.de.
authors.forename: Richard
authors.initials: R
authors.lastname: Henze
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000235:genetics*; D001693:Biological Transport, Active / Q000235:genetics* / Q000502:physiology; D064199:Cdc20 Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D003600:Cytosol / Q000502:physiology; D006801:Humans; D018386:Kinetochores / Q000502:physiology*; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D064246:Mad2 Proteins / Q000235:genetics*; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics
chemical_list: D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D064173:Anaphase-Promoting Complex-Cyclosome