02.23.11Lecture 15 - Mitosis

M for mitosis

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Mitosis is the process that partitions replicated chromosomes equally to 2

daughter cells

Mitosis proceeds through 6 stages

Cytokinesis

Successful mitosis requires the precise coordination of many processes

• Packaging of the genome into mitotic chromosomes

• Regulation of microtubules and motors to build spindle

• Disassembly of the nuclear membrane

• Attachment and movement of chromosomes on the spindle

• Cleavage of a cell into 2 daughters

Interphase - late G2

• DNA is duplicated• Cell has doubled in

size• Centrosome has

duplicated• M-cyclin levels high

Prophase

• Chromosomes condense

• Nuclear envelope breaks down

• Microtubules reorganize to make asters

• Centrosomes move to opposite sides of the cell

Replicated chromosomes are prepared for segregation by cohesins and

condensins

• Cohesins hold sister chromatids together

• Cohesins are deposited on chromosomes during S-phase

Replicated chromosomes are prepared for segregation by cohesins and condensins

• Condensins bind to chromosomes in prophase

• Molecular motors that “wind” chromatin into small physical packets for mitosis

The nuclear envelope breaks down and re-forms during mitosis

Dynamics of the nuclear envelope during cell division

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Prometaphase

• Chromosomes are captured by microtubules at the kinetochore

• Chromosomes undergo active movement oscillating back and forth on the spindle

• Kinetochores of each sister chromatid captured by microtubules from each pole

Centrosomes organize the microtubules in a mitotic spindle

Microtubules are the core structural component of the mitotic spindle

Changes in microtubule dynamics contribute to spindle assembly

Interphase Mitosis

Growth rate Intermediate Low

Shrinkage rate Intermediate High

Frequency of catastrophe

Low High

Three sets of microtubules make up the mitotic spindle

Bipolar spindles are formed by the selective stabilization of interacting microtubules

• Microtubules grow in random directions

• Overlapping microtubules from opposite poles are cross-linked and stabilized by MAPs and motor proteins

Microtubule dynamics are regulated by associated proteins

• Microtubule-associated proteins (MAPs) stabilize microtubules in interphase, but are phosphorylated in mitosis and decrease their stabilizing effects

• Catastrophins are proteins that destabilize microtubules, their activity is upregulated upon entry into mitosis

Kinetochores attach chromosomes to the mitotic spindle

Capture of centrosome microtubules by kinetochores

Metaphase

• Chromosome congression to the metaphase plate

• Paired kinetochore microtubules on each chromosome are attached to opposite poles of the spindle

• Mitotic checkpoint ensures the fidelity of this bi-polar attachment

Unattached kinetochores mediate the mitotic checkpoint

Checkpoint: spindle assembly

• Mitosis must not complete unless all the chromosomes are attached to the mitotic spindle

• Mitotic checkpoint delays metaphase to anaphase transition until all chromosomes are attached

• Prolonged activation of the checkpoint -->cell death

• Mechanism of many anti-cancer drugs

Anaphase

• M-cyclin is destroyed• Paired chromatids

simultaneously separate to form 2 daughter chromosomes

• Each chromosome is pulled to the pole to which it is attached

• Kinetochore MTs shorten - anaphase A movement

• Spindle elongates - anaphase B movement

APC triggers the separation of sister chromatids by tagging cohesins for destruction

Anaphase chromosome movement is driven by 2 processes

Spindle elongation during anaphase B is mediated by motor proteins

Microtubule attachment sites in a kinetochore are thought to form a sliding collar

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Kinetochore movement at the metaphase-to-anaphase transition

Telophase

• The 2 sets of chromosomes arrive at the spindle pole and begin to decondense

• Nuclear envelope begins to reform

• Cleavage furrow begins to form around circumference of the middle of the 2 daughter cells

Cytokinesis

• The division of the cytoplasm is completed by the contractile ring

• Cells re-enter interphase in G1

• Microtubules reform their interphase organization

Cytokinesis is the process by which the cytoplasm is cleaved in two

The cleavage furrow of the plasma membrane is formed by the action of the contractile ring.

The contractile ring divides the cell in two

Organelles are segregated to each daughter cell during mitosis

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Golgi apparatus partitioning during mitosis