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Chromosomes and Mitosis
Lecture 6
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1 Chromosomal Basis of Heredity• A gene is a unit
of heredity• Genes are
carried on DNA• DNA is
contained within chromosomes as chromatin
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Chromosomes replicate during cell division
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The chromosome complement
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Chromosome analysis
Cri Du Chat results from loss of a small piece of chromosome 5
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Gene Map
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Chromosome pairs
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Non-identical genes
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Sex chromosomes
• These determine the sex of an individual– Two X chromosomes make a female
– One X and one Y a male
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Two types of Cell Division
• Cells divide for two reasons– To create genetically identical
copies of themselves• This is
mitosis
– To create gametes that contain half of the chromosomes of the original cell
• This is meiosis
46
46 46
46
23 23 23 23
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The Cell Cycle
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S phase
ReplicationCondensation
Schematic
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DNA replication
Duplex DNA begins Replicating
Replication bubbles merge creating two duplexes
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Mitosis
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The stages of Mitosis
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Prophase Detail
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Prometaphase
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Metaphase
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Anaphase
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Telophase
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The sum total of the process
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Karyotypes
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Chromosome Length
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Chromosome appearance
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Meiosis and Gametogenesis
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Somatic and Germline cells
• Development of a fertilized egg into an adult results in two distinct types of cells– Somatic cells
• These create all tissues and organs of the adult except for cells destined to become sperm or egg
• They can only undergo mitosis
– Germline cells• The final differentiated form of these cells are mature gametes:
the sperm and egg
• These cells undergo mitosis until gametogenesis– They then undergo meiosis
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Meiosis
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Meiosis is required for gametogenesis
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Meiosis ISomatic cells
Germline Cells
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Interphase I and Prophase ILeptotene
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Prophase IZygotene
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Prophase IPachytene
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Prophase IDiplotene
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Recombination
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And on the molecular level
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Metaphase I and
anaphase I
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Meiosis I is the reduction division
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Non-disjunction
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Telophase I
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Cytokinesis
sperm formation oocyte formation
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Meiosis II
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A comparison of meiosis and
mitosis
Mitosis Meiosis
Chromosome number
Maintains Reduces
Nuclear Divisions 1 2
Cells resulting 2 4
Cells involved Somatic Germline
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Relationship to Gametogenesis
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Sperm and Egg formation
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Gametogenesis
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Fertilization
• Entry of a single sperm into an egg prevents entry of other sperm
• The DNA of sperm and egg are initially kept separate in “pronuclei” of the zygote
• Timing of a pregnancy extends from the “last menstrual period” (LMP) rather than the time of fertilization
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Mitotic Non-disjunction
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Cell cycle and apoptosis• Cells undergo 3 controlled processes
– The first two are part of the cell cycle, the last an exit from the cell cycle
– Division (the cell cycle)– Quiescence
• This is where most of the work of being a cell lies– During division the energy of the cell is devoted to making a new cell
– Death• This can be a normal process creating a final functional form or an induced
suicide– Epithelium and reticuloendothelial cells undergo active transitions towards
terminally differentiated states in which the final forms are unable to divide» The stratum corneum consists of cells that have become bags of
crosslinked keratin protein with no internal metabolism– Suicide can be induced because the organism senses a threat to the entire
organism» Infection, cancer, avoidance of autoimmunity
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Control of entry into cell cycle and apoptosis
• Cell cycle is initiated by phosphorylation of transcription factors
• These activate transcription of a set of proteins known as cyclins
• The appearance of cyclins is progressive and determines the types of proteins that will be phosphorylated at a particular point during the cell cycle
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Cyclins and CDK’s• CDK levels don’t
change while cyclins are destroyed at the end of each phase
• There are 3 general groups of each– G1 cyclins
• Cyclin D
– S-phase cyclins• Cyclin A
– G2 cyclins• Cyclin B (maturation
promoting factor MPF)
– Cyclin E is shared between G1 and M phase
– Cyclin A is shared between M phase and G2
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Cyclins bind CDK’s • CDK’s are Cyclin
Dependent Kinases• Association with cyclins
activates their kinase function– A cyclin tethers a target
protein to the CDK
• The targets of CDK’s are transcription factors among other proteins– CDK’s are serine/threonine
kinases
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The exit from Go
• Go is a quiescent state• Activation of G1 CDK
occurs due to a rising level of G1 cyclins
• G1 cyclins are transcriptionally activated by growth factors
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Events during G1
• A rising level of G1 cyclins increases the activity of G1 CDK’s
• CDK’s in turn activate proteins and in turn genes that prepare the cell to begin DNA replication
• At the G1 S boundary, the cell encounters a checkpoint
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G1/S checkpoint
• This is controlled by the activity of the transcription factor E2F– E2F is a family of related proteins (E2F 1 to
E2F5)
• E2F is found complexed throughout the cell cycle to another family of proteins: Rb– At the G1/S checkpoint, Rb is
phosphorylated by CDK2/cyclinA– E2F is freed from sequestration and activates
transcription at genes containing an E2F consensus sequence
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And those genes are• Three groups
– Cell cycle regulators• Cyclin A• E2F, Rb, myc, myb
– Note that these are not all positive regulators of cell cycle
– Enzymatic machinery for DNA synthesis
• DNA polymerase• PCNA• Enzymes involved in
nucleotide metabolism
– DNA synthesis regulators• Enzymes that recognize the
origins of replication for example
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Other Checkpoints
• These monitor the completion of DNA synthesis– The presence of Okazaki
fragments prevents entry into G2
• DNA damage – This occurs before, during and
after completion of S phase
• Spindle attachment– Failure to attach spindle to
centromere results in blockage of mitosis at metaphase
– Failure to align the spindle during cytokinesis results in blockage at anaphase
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Downregulation of cyclin influenced
CDK activity
• This is accomplished through proteolysis of the cyclins– G1 phase cyclins disappear during S
and G2 phase
– M-phase promoting factor (CDK2 + cyclin B) concentrations rise just prior to onset of mitosis
• Cyclins associated with MPF are degraded by anaphase promoting complex
– Cyclin B levels peak at G1/M
» Degradation during anaphase
– APC promotes polyubiquitination of cyclin B
– Ubiquitinated cyclin B is degraded by a proteosome
• Cyclin transcription is also turned off and the mRNA is unstable– So no new cyclin is made until
transcription is restored
cyclin B
cyclin A
ribonucleotidereductase
Mitosis MitosisInterphase Interphase
Time
Newly synthesized proteins labeled with 35S-methionine:
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MPF activates APC which
ubiquitinates cyclin B
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In the overall• Stimulated entry into G1
results in appearance of an initial level of cyclins that promote the progressive activation of genes enabling the cell to synthesize DNA
• A series of progressive steps result in– Activation of genes further
into the cycle
– Degradation of cyclins that promoted earlier steps
– Passage through checkpoints that insure mechanistic fidelity of each step
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Apoptosis (apo – toe – sis)
• This is programmed cell death– Distinguish it from necrosis
– Necrosis results from traumatic forces outside the cell
– Necrotic tissue provokes inflammation as the immune system moves in to clear out damaged and dead cells
• Apoptosis is an ordered stepwise self-destruction that permits surrounding cells to utilize the breakdown products of the dead cell– There is no inflammation involved
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The apoptotic cell
• Mitochondria break open
• DNA fragments in a regular way
• The cell loses a regular shape– Undergoes blebbing– This is an irregular
bubbling appearance of the plasma membrane
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The mechanisms of apotosis
• Can be classified as externally or internally signaled
• One internal route involves p53
• p53 is a transcription factor that is involved in cell cycle control and sensing the presence of DNA damage
• The central role p53 plays is at the G1/S checkpoint
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P53 controls entry into S-phase• P53 can sense DNA damage by binding mismatches
• In the presence of damage, p53 activates transcription of p21– P21 binds and inactivates CDK2-cyclin E complexes
– The complex is unable to phosphorylate Rb and free E2F
– Thus entry into S phase is inhibited
– If the damage is repaired, p53 levels and p21 levels drop and S phase ensues
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But if the DNA damage is extensive
• P53 induces apotosis by activating transcription of Bax– BAX protein competes with BCL-2 to form
pores in mitochondrial membranes• BCL-2 prevents the release of cytochrome c from
mitochondria into the cytoplasm• BAX permits release of cytochrome c
– When released, cytochrome c stimulates caspase activation
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The caspases
• These are proteolytic enzymes that are held in check by external or internal inhibitors
• Activation results in an explosive proteolytic cascade– Caspase 9 cleaves and
activates other caspases
– The caspases also activate quiescent nucleases
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External apoptotic mechanisms
• Involve external “death signals”
• Cells may be recognized as a threat to the whole organism– The immune system moves
in to kill them
– One mechanism of killing involves a command to the cell to initiate apoptosis
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Fas/Fas ligand signaling
• Fas ligand (FasL) is a membrane bound cell surface protein
• It binds to Fas receptor• Binding results in trimerization
and activation of APAF• APAF in turn activates caspase 8
by proteolysis of a caspase 8 zymogen– Caspase 8 cleaves a BCL-2 family
member BID– BID translocates to the
mitochondria and binds BAX– Bax permits leakage of cytochrome
c and activation of the caspase 9 cascade via APAF-1 again