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8/10/2019 10. the Cell Cycle ABC 2009
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The Cell CycleMitosis
Tbilisi State Medical UniversityDepartment of Medical Biology and Parasitology
Gocha Shatirishvili2009
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The Cell Cycle
Self-reproduction is one of the mostfundamental characteristic of cells
Each parental cell giving rise to twodaughter cells
Repeated cycles of cell growth and division -development of a single fertilized egg intothe more than 10 14 cells of human body
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The Eukaryotic Cell Cycle
1.
Cell growth
2. DNA replication
3. Distribution of the duplicatedchromosomes to daughter cells
4. Cell division
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Phases of the Cell Cycle: Mitosis and Interphase Mitosis (nuclear division) - separation of daughter
chromosomes and cell division - cytokinesis
Mitosis and cytokinesis last only about an hour
Interphase the period between mitoses
During interphase the chromosomes aredecondensed and distributed throughout thenucleus and cell growth and DNA replicationoccur
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The cell grows at a steady ratethroughout interphase
DNA is synthesized during onlya portion of interphase
The timing of DNA synthesis
thus divides the cycle ofeukaryotic cells into fourdiscrete phases
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The M phase - mitosis
G1 phase (gap 1), the interval
between mitosis and initiation ofDNA replicationcell is metabolically active GrowthNo DNA replicatation
S phase (synthesis) - DNAreplication
G2 phase (gap 2), cell growth,proteins synthesis -preparation
for mitosis
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Human cell with a total cycle time of 24 hours, theG1 phase about 11 hours, S phase - 8 hours, G2 - 4hours, and M - 1 hour
Cell cycles of early embryo cells shortly afterfertilization - 30 minutes no cell growth , divisioninto smaller cells, no G1 or G2 phase, DNAreplication occurs very rapidly =very short Sphases alternating with M phases
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Cells at different stages of cell cycle can be distinguished by DNAcontent
G1 - containing two copies of each chromosome (diploid) S phase , replication increases the DNA content of the cell
from 2 n to 4 n
DNA content then remains at 4 n for cells in G2 and M,decreasing to 2 n after cytokinesis Cellular DNA content is determined by fluorescent dye that
binds to DNA, followed by analysis of the fluorescenceintensity of individual cells in a flow cytometer
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B lymphoma cells in S and G2/M phases
f
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Regulation of the Cell Cycleby Cell Growth and
Extracellular Signals
Cell cycle isregulated byextracellular signals (growth factors) fromthe environment, as
well as by internalsignals
Cell growth, DNAreplication, andmitosis, arecoordinated by aseries of controlpoints
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Restriction Point Cells enter in the cell cycle is
regulated primarily by the
extracellular growth factors thatsignal cell proliferation
Decision point in late G1, called therestriction point in animal cells
Restriction point is the point at whichcell growth is coordinated with DNAreplication and cell division.
In the presence of theappropriate growth factors ,cells pass the restriction point and enter S phase
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Once cell has passed through the restriction point,
the cell enter in S phase, even in the absence offurther growth factor stimulation
If appropriate growth factors are not available inG1, progression through the cell cycle stops at therestriction point
Such arrested cells then enter a quiescent stage ofthe cell cycle called G0, in which they can remainfor long periods of time without proliferating.
G0 cells are metabolically active, although theycease growth and have reduced rates of proteinsynthesis
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Some cell cycles are controlled inG2: oocytes
Vertebrate oocytes can remain
arrested in G2 for long periods oftime (several decades in humans ) until their progression to M phase is
triggered by hormonal stimulation
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C ll l h k i t th t i l t
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Cell cycle checkpoints ensure that incomplete ordamaged chromosomes are not replicated andpassed on to daughter cells
G2 checkpoint prevents the initiation of mitosis
until DNA replication is completed.
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Loss of p53 function as a result of thesemutations prevents G1 arrest in response toDNA damage
Damaged DNA is replicated and passed onto daughter cells instead of being repairedand results cancer development.
Mutations in the p 53 gene are the mostcommon genetic alterations in humancancers
C li g f S Ph t M
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Coupling of S Phase to MPhase
DNA replication is restricted to
once per cell cycle by MCMproteins that bind to origins ofreplication of DNA together withORC (origin replication complex) proteins in G1, allowing DNA
replication to initiate in S phase
Once initiation has occurred, theMCM proteins are displaced andreplication cannot initiate again
until after mitosis
These controls prevent cells in G2from reentering S phase
.
Th E t f M Ph
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The Events of M Phase-Mitosis (nuclear
division)1. Chromosome condensation
2. Formation of the mitoticspindle
3. Attachment of chromosomesto the spindle microtubules
4. Sister chromatids separationfrom each other and move to
opposite poles of the spindle
5. Formation of daughter nuclei
6. Cell division
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Mitosis
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P h
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Prophase The appearance of
condensed chromosomes
The condensed sisterchromatids are held togetherat the centromere , DNAsequence to which proteinsbind to form the
kinetochore the site ofeventual attachment of thespindle microtubules
The centrosomes incytoplasma separate andmove to opposite sides ofthe nucleus
They serve as the two polesof the mitotic spindle
Prometaphase
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Prometaphase Prometaphase-
transition period
between prophaseand metaphase.
Duringprometaphase themicrotubules of themitotic spindle attach to thekinetochores ofcondensedchromosomes.
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Metaphase and Anaphase Breakage of
the link
between sisterchromatids,separation andmove toopposite polesof the spindle
T l h N l i f d
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Telophase Nuclei re-form andthe chromosomesdecondense
Cytokinesis beginsduring lateanaphase and isalmost completeby the end oftelophase-
formation of twointerphasedaughter cells
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The condensation
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The condensationof interphasechromatin a
thousand fold Protein complexes
-condensins causecondensation bywrapping DNAaround itself
The condensinsare phosphorylateddirectly by theCdc2 proteinkinase
Breakdown of the nuclear envelope
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Breakdown of the nuclear envelope
Cdc2 phosphorylates the lamins depolymerization of nuclear lamina andfragmentation of the nuclear membrane
These fragments form new daughter nuclei at
telophase
The endoplasmic reticulum and Golgi apparatus
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The endoplasmic reticulum and Golgi apparatusfragment into small vesicles, which are bedistributed to daughter cells at cytokinesis .
Golgi matrix protein GM130 is p hosphorylated byCdc2 , leading to fragmentation of the Golgi apparatus.
MPF activity induces a depolymerization andshrinkage of the interphase microtubules byphosphorylation of microtubule-associatedproteins
Interphase microtubules are replaced by largenumbers of short microtubules radiating from thecentrosomes
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Proteolysis and theInactivation of MPF
After completion of mitosis MPF is degraded byubiquitin-mediated proteolysis , triggered byubiquitin ligase : anaphase-promotingcomplex
Activation of the anaphase-promotingcomplex is induced by MPF at the beginningof mitosis - MPF ultimately triggers its owndestruction
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Activation of the anaphase
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Activation of the anaphase-promoting complex leadsto the degradation of atleast two key regulatoryproteins : Scc1 , acomponent of a complex of
proteins called cohesins (that maintain theconnection between
sister chromatids ) viadegradation of of Pds1 andactivation Esp1
C yclin B -targeted for
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C yclin B targeted forubiquitination anddegradation by the anaphase-promoting complex
Degradation of cyclin Bleads to inactivation of MPF and cell to exit mitosis andreturn to interphase.
Reassembly of the nuclearenvelope
Chromatin decondensation The return of microtubules to
an interphase state are resultof MPF activity loss