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Mitotic Spindle Assembly Checkpoint (MSAC). System View Communication model Quantitative observations Biophysical models Molecular models. System View Communication model Biophysical models Molecular models. Basic schema of SAC. Balance between:
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Mitotic Spindle Assembly Checkpoint (MSAC) System View Communication model Quantitative observations Biophysical models Molecular models
System View Communication model Biophysical models Molecular models
Basic schema of SAC • Balance between: • An inhibitory signal to prevent anaphase • Unattached kinetochores generate signals that prevent the onset of anaphase (Silenced If properly connected to microtubules ) 2.The activity of anaphase-promoting machinery - APC(anaphase-promoting complex, activated by cofactor Cdc20)
Focusing observations • The SAC can delay anaphase in response to a singleuncaptured chromosome, exhibiting excellent sensitivity • Quick disengagement of the spindle assembly checkpoint once all kinetochores are attached • Highly-reliable process
System View Communication model Quantitative observations Biophysical models Molecular models
Convert into Communication System • A transmitter (spindles) consistently sent out PCK (microtubules) • Consider the duplicated chromesome as receiver with multiple receiving antennas, not until all the antennas send out ACK does the PCK consider received by the transmitter.
Our approaches • Think without pre-knowledge of biology • Redefine “information” • How the last kinetochore can still be effective
System view of SAC Break SAC into three major modules • The kinetochore-localized signalling platform • The spindle attachment machinary • Cytoplasmic activities associated with APC activities.
System View Communication model Quantitative observations Biophysical models Molecular models
System View Communication model Quantitative observations Biophysical models Molecular models
Biophysical Models • Only one unattached kinetochore Focus on two properties of the checkpoint: 1 .The extent of cell-cycle inhibition at steady-state 2. The time it takes to increase the level c back to 90% of its maximum.
General Framework • c = the protein that triggers cell-cycle progression • ρ = radius of a kinetochore = 0.01μm • R = radius of a nucleus = 1 μm • Ac = the capacity of the checkpoint to inhibit the c protein (quantified by the steady-state fraction of uninhibited c, the smaller the Ac, the more efficient.) • Tb = the time it takes to increase the level c back to 90% of its maximum. • Assumptions: Tb < 3min ; Ac < 0.05
Direct inhibition model • Once a c molecule hits the kinetochore region, it becomes immediately inhibited (c*) • Result: Cannot support good inhibition while maintaining rapid reactivation time
Self-Propagating inhibition Model • An inhibited c* can bind at some rate k to an uninhibited c molecule and catalyze its inhibition. • Result: Although the inhibition is sufficiently high, the system also remains inhibited upon the binding of the last kinetochore
Emitted inhibition Model • Inhibition doesn’t occur solely on the kinetochore but that the kinetochore catalyze the formation of an inhibitory complex e that can diffuse away form it and inhibit the c molecule everywhere. • Activation of e occurs on the kinetochore, inactivation occurs either spontaneouly or by interaction with c
Pros and Cons of Biophysical Models • Provide an important function in testing hypotheses rather than revealing specific pathways • Biophysical Models are useful to understand the systems level behavior but cannot provide a clear connection to molecular mechanism
System View Communication model Quantitative observations Biophysical models Molecular models
Molecular Models • Mad2 Template model (Mad1/Mad2 sequester) -Cdc20 captured by Mad2 • MCC formation -Mad2:Cdc20 + Bub3:BubR1 => MCC • APC inhibition MCC+APC= MCC:APC (inactive) APC:cdc20 complex is the key to separate.
Scc1 holds the two chromatids attached • Separase protease, Esp1, degrades the cohesion. • Securin protein keep Esp1 inactive.