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