DNA Repair, CellCycle Regulation, Apoptosis, Cancer
Honors Biology
DNA Packaging -review
Chromatin form of DNA. Found in interphase or G0 cells
Chromosome conformation required for cell division
DNA RNA protein Selective Pressure: Altered DNA could lead to altered
protein function Un-repaired errors or damage = mutation Mutation = any permanent change in DNA structure
or base sequence Chemicals and radiation (mutagens) Errors in replication
Part 1: Why Repair DNA?
Sources of Error
Neutral usually, Deleterious sometimes, Beneficial
rarely. Mutations that occur in germ cells may be passed on
to sperm or eggs, and on to offspring. Raw material for Natural Selection and Evolution
Mutations that occur in somatic (body) cells are not passed to offspring
Results of Errors
Frequency
1/10,000 before repair 1/10,000,000 after repair Higher rate in viruses
Other Causes of Mutation Mutagens: chemicals or
radiation that cause alterations in nitrogenous base structure
May result in “mismatches”
Mutation During Replication
DNA polymerase proofreading function
Most errors by DNA polymerases are corrected Enzyme goes back and inserts correct base!
Methods of Repair
Methods of
Repair Excision Repair
Mismatch identified Short region
containing mismatch is excised
DNA pol I replaces missing bases
Ligase forms bonds in S-P backbone
Apoptosis
= Programmed Cell Death, PCD
It is the default program in all dividing cells: If something goes wrong, apoptosis pathway is activated.
Why is this an adaptation?
There are two different reasons.
1. Needed for proper development. Menstrual cycle Digits Bone remodeling
2. Needed to destroy cells that threaten the organism. Unrepaired DNA damage Unbalanced growth signals Virus infection
Why apoptose?
A signal from inside or outside the cells causes
caspases (proteases) to be activated in a cascade
Lipases are activated Cellular stuctures are digested Macrophages endocytose the pieces
What happens during apoptosis?
White Blood Cell
Apoptosis
How is apoptosis an example of each?
Living systems transmit and respond to information.
Living systems interact with one another and their environment.
Living systems use energy to maintain homeostasis.
Big Themes in Biology:
Control of Cell Cycle
Frequency of cell division varies by cell type
Embryo Cell cycle < 20 minutes
Skin cells Divide frequently throughout life (12 – 24 hrs)
Liver cells Retain ability to divide. (G0)
Mature nerve and muscle cells Do not divide Permanently in G0
Control of the Cell Cycle
How does a healthy cell know when to divide?
Whether or not to proceed to the next phase is
under tight control Chemical signals
Internal – cyclins and cdk’s, check points External – Hormones, growth factor
Environmental conditions Over-crowding (space and nutrition requirements) Attachment requirement Barrier of other tissues.
Proceed v. Stop and Repair v. Apoptosis?
Control of the Cell Cycle
How does a healthy cell know when to divide?
Control of Cell Cycle
Cyclin concentration in the cytoplasm varies
throughout the cell cycle
Cyclins
A kinase adds phophate groups to a protein The addition of phosphate groups may
activate or inactivate a protein A cyclin-dependent kinase is only active when
it is complexed with a cyclin. CDK concentration is constant throughout cell
cycle
CDKs: Cyclin-Dependent Kinases
The cyclin-cdk’s phosphorylate target proteins. In turn, target proteins act on other proteins
controlling cell cycle The target proteins may
Halt the cell cycle temporarily Activate DNA repair enzymes Fix spindle attachment Induce apoptosis Induce cyclin degradation (negative feedback
loop)
Functions of cyclin-cdk complexes and target proteins
Example: p53
These proteins cause cell cycle arrest, induce DNA repair or apoptosis.
When the genes encoding these proteins are mutated, the cell cycle cannot be controlled and
Cancer probablility is increased
Cdk’s have Important Targets
Cancer
Uncontrolled Cell Division
Uncontrolled cell division “immortalized” or
“transformed” cell, a cancer cell Tissue damage as a result of uncontrolled cell
division pathology of cancer, the disease state
What is Cancer?
Metastasis = spread, n. (Metastatic = spreading,
adj.) A more general feature of dangerous solid
tumors, therefore a promising area of research Metastasis is what causes tissue damage and
organ failure In contrast, many cancers of the immune system
circulate in blood and lymph. They cause damage by crowding out other types of blood cells.
Metastasis of solid tumors
Blood cells leukemias or lymphomas Muscle or bone sarcomas Connective tissue carcinomas Nervous tissue glioma, for example
etc. Each disease has different
Etiology Symptoms Treatments
Each patient has a unique set of cancer cells, a unique set of mutations, a unique disease
Many different types of Cancer
Our analogy: A car driving out of control
Original concepts credited to Fearon and Vogelstein’s model of colon cancer etiology
The Etiology of a Dangerous Solid
Tumor
Cell cycle is contolled by balance of positive
and negative growth signals, from both inside and outside the cell.
Cancer cells cease to respond to growth signals properly.
The environment is providing traffic lights, road signs and lane markers, but the driver of the car is not paying attention.
Watch the road, please?
Progress through the cell cycle results
from normal expression of protooncogenes = the gas pedal
Normal functions: transmit + growth signals, turn other on genes
When mutated, protooncogenes become oncogenes, = cancer genes. The cell will continue past the Restriction
Point because of constant “on” signal
The gas pedal is stuck to the floor!
Response to + growth signals
Negative growth signals lead to expression of Tumor Suppressor Genes = the brakes Normal function: Surveyors and checkpoint
proteins, they arrest the cell cycle for repair or apoptosis.
p53 and Rb are most important When tumor suppressor genes are mutated,
checkpoints fail.
The brakes don’t work!
Response to - growth signals
Mutation in DNA repair enzymes is a common
feature New mutations may accumulate with each cell
cycle
The mechanic is a putz!
Repair, please?
Imbalance of growth signals or unrepaired
DNA should lead to apoptosis BUT in cancer cells, at least one of the genes
controlling apoptosis pathways has been mutated, no caspase activation occurs.
The steering wheel doesn’t work either! Can’t turn the car toward the cemetery!
Apoptose, please?
Cells need nutrients and oxygen and waste removal. Normal tissues are vascularized, capillaries nearby. Tumors should be dead in the middle, no capillaries. Tumors usually stay very small But, dangerous solid tumors have mutated
expression of vascular growth factor genes. They send signals out, calling for growth of blood vessels into the tumor. “FEED ME!” We don’t need no gas! We got our own supply line!
Run out of gas, please?
Angiogenesis brings
nourishment
Cells respond to external
signals from the environment: It’s getting crowded Anchorage requirement –
normal cells will grow to 1-cell layer thickness in a petri dish. Cancer cells will pile up.
Nutrient requirements
Keep all 4 tires on the road, please?
The immune system sees the cancer cell as “self”
for the most part, because it comes from the same individual. It’s not a foreign invader.
Immune system kills cancer cells that look different, but normal-looking variants are ignored.
Natural selection and clonal expansion Patient’s immune system selects normal-looking
cancer cells for survival and expansion.
The police can’t see that the driver is criminal, can’t trace the license plates.
Shouldn’t the police pull over this wreck?
Cancer cells dissolve tissue barriers (extracellular
matix and encapsulating membranes). Mutations in genes encoding enzymes that normally
remodel tissue, allowing spread and invasion. This is the basis of metastasis, spread of the tumor
into other tissues, near and distant.
These cars dissolve concrete barriers and brick walls, pushing through unscathed.
Cars that drive where they shouldn’t can cause a lot of damage.
Hit a dead end, please?
Metastasis enables
spread
Normal cells have a limited number of cell
divisions (50?) before they apoptose, because With each round of cell division, their telomeres
(chromosome ends) get shortened. Some cancer cells express the telomerase
gene, inappropriately, and maintain telomere length.
The cell cannot sense its own age. Don’t take my keys away, junior! I’m young, for
Florida!
Die of old age, please?
Telomerase repairs chromosome ends
A typical cancer cell accumulates mutations that may
Activate oncogene(s) Inactivate tumor suppressor gene(s) Mutate DNA repair enzyme(s) Mutate apoptosis control gene(s) Induce vascularization Evade the immune system Digest/dissolve tissue barriers (metastasis of solid
tumors) Reactivate telomerase = become immortal Alter chromatin structure
Review: Cancer Cell Etiology
Cancer incidence increases with age.
Why?
A Disease of the Aged
How is each guiding concept altered in
the metastatic tumor? The theory of evolution explains both the
diversity and unity of life. Living systems use energy to maintain
homeostasis, grow and reproduce. Living systems store, utilize, transmit and
respond to information. Living systems interact with one another and
their environment.
Guiding Concepts of Biology and the Disease
State