Lecture 6

Question 1

What are the 3 processes that occur after damage to the DNA?

Answer 1

1. Perfect repair
   (if this is NOT successful, then there are two other outcomes:
2. Misrepair
   : accumulation of mutations which leads to cancer.
   3.) Toxicity
   : can be repaired - apoptosis

Question 2

2 DNA Physical factors

Answer 2

1. Ionising radition eg. x-rays
2. Ultralight radiation

Question 3

What happens in ionising radition?
Toxicity and misrepair:

Answer 3

Undergoes hydrolysis, forming free radicals which break the DNA double bind and they are detected by proteins.
Toxicity: (repairable) Acute damage to endothelial cells - surrounding cells die/tissures shrink (atrophy), ulceration, bleeding, and scarring.
Misrepair: Leads to chromosome translocations –> leads to blood cancers

Question 4

What happens in ultraviolet radition?
Toxicity and misrepair:

Answer 4

Pyrimidine crosslinking in DNA –> forms DNA adducts.
Toxicity: acute damage to keratinocytes
Misrepair: mutations = skin cancer (maligent melanoma)

Question 5

DNA Chemical factor example:
Explain why and how
Toxicity and misrepair:

Answer 5

Aflatoxin (eating poorly stroed food)
DNA adducts, G to T transversions.
Toxicity: Damage in the hepatocytes (main cells making up the liver) - at high doses
Misrepair: Chronic low doses can lead to liver cancer (hepatocellular carcinoma)

Question 6

DNA Biological factor example:
Explain why and how
Toxicity:

Answer 6

Dietary deficiency Eg. folic acid
: Vitamen B9 and B12 needed for correct DNA synthesis/repair. Essential to make thymine and methionine (amino acid proteins)

Misreapir: Lack of protein = intrisic factor in autoimmine gastristics which prevents B12, developing megaloblastic anaemia (incorrect development of RBC)

Question 7

Lipids: Physical example (ripping lipid apart)

Answer 7

Crystals

Question 8

Lipids: Chemical example

Answer 8

Oxidants (ROS)
- Many forms of reactive oxygen species (ROS)

Question 9

ROS (reactive oxygen species) are generated:

Answer 9

• essential intermediates in other enzyme reactions
• neutrophils release ROS to kill invading bacteria
• cells exposed to hypoxia/hyperpoxia generate ROS

Question 10

ROS function

Answer 10

They act as signalling molecules to promote DNA replication and cell proliferation.

Question 11

What happens if there is damage to lipids?

Answer 11

Lipid peroxidation eg. unsaturated fatty acids in membrane phospholipids.

Question 12

Effects of lipid peroxidation:

Answer 12

• increased membrane rigidity
• decreased activity of membrane bound enzymes (Na+ pumpps)
• altered activity of membrane receptors
• altered membrane permeability (more/less leaky)

Question 13

Key ROS enzymes

Answer 13

1. Superoxide dismutase (SOD) converts superoxide anion radical into O2 and H peroxide
2. Catalase converts H peroxide into water and O2
3. Hydroxyl radicals react with lipid hydrogens –> lipid peroxidation

Question 14

Lipids: Biological example

Answer 14

Lipases Eg. organ damage

Question 15

ROS can injure cells. What are some examples?

Answer 15

• O2 therapy given to premature babies can lead to lung damage.
• Inflammation mediated by macrophages and neutrophils during infection.
• UV radiation excites molecules which transfer energy/electrons to O2 and cause skin damage.
• Ionising radiation (radiotherapy) induces hydroxyl radicals.

Question 16

What is glycation

Answer 16

Adding sugar molecules to proteins.
primary amine –> schiff base –> amadori product => Advanced glycation end products (AGE)

Question 17

Proteins: Physical

Answer 17

Heat eg. sunstroke

Heatstroke, fever and hyperthermia lead to protein denaturation (esp in the brain). Leads to inflammation, ischemia, haemorrhage, oedema.
→ fever is a mechanism the body uses during inflammation which can be steroidal or infectious inflammation.

Question 18

What happens if there is an increase of heat stroke proteins?

Answer 18

1. Bind to denatured proteins
2. Stop their aggregation
3. Aid in renaturation
4. Promote proteolytic destruction of proteins that are too damaged

Question 19

Proteins: Chemical

Answer 19

Glycation eg. sugar

Question 20

Advantage glycation end products (AGE)

Answer 20

• They inhibit protein function
• Form ROS
• Cause protein to cross-link and become insoluble (precipitate)
• Binds to RAGE receptors to reduce blood flow and cause inflammtion

They are harmful compounds that form when proteins/ fats combine with sugar in the bloodstream, a process that accelerates with age and high sugar intake

Question 21

What chronic diseases does AGE form?

Answer 21

Diabetes (more sugar available), cardiovasculasr disease, alzheimer’s, cataracts (in the lens)

Question 22

Proteins: Biological

Answer 22

Proteases
: they change shape, location and function of cells

eg. inflammation
- They release ROS to kill any bacteria
- In sterile inflammation, they mop up any damaged cells.

Question 23

Proteases cause what types of chronic diseases?

Answer 23

Arthritis - cleaved collagen in joints
Emphysema - cleaved elastin in the lung extracellular matrix
Cancer invasion - cleaved laminin allows cancer cells to migrate

Question 24

Reversible injury:
What are the three reversible effects?

Answer 24

Cells adapt, survive and recover.
1. Acute intracellular oedema
2. Abnormal storage
3. Adaptive response

Question 25

Acute intracellular oedema:

Answer 25

- plasma membrane becomes permeable to Na+ (via membrane lipid peroxidation) - The Na/K+ ATPase pump is damaged - ATP synthesis disrupted, decreasing ATPase pump activity - Na+ leaks into the cells and K+ leaks out of the cell. This osmotic balance causes cells to swell as water follows Na+ into the cell reversibly (can replace damaged cells)

Question 26

In intracellular oedema, if ATP is absent and cells lack energy they continue to swell. If it becomes to extensive what happens?

Answer 26

accidental cell death = oncosis

Question 27

Abnormal storage example:

Answer 27

Liver hepatocytes normally take up fatty acids from the blood and convert it to triglycerides for storage until needed

Question 28

Is abnormal storage reversible?

Answer 28

Yes, by the removal of fatty acids or addition of drugs that can clear triglycerides

Question 29

Pathologies that disrupt the normal process of storage of triglycerides:

Answer 29

- Diabetes: increased conc. of fatty acids - Alcohol :damages hepatocyte mitochondrial capability to breakdown triglycerides - Kwashiorkor - severe malnutrition, inability to export triglycerides

Question 30

Adaptive responses to stress process

Answer 30

Cellular sensors for a stress factor --> switches on specific genes (transcriptional programmes) to allow the cell to adapt by making proteins to change cellular functions. (when signal goes away, they revert back to normal).

Question 31

What senses damage to the DNA?

Answer 31

DNA damage response (DDR) which is driven by p53 ( which detects breaks in DNA strands)

Question 32

p53:

Answer 32

: It detects breaks in the DNA strands. - It induces proteins involved in cell cycle arrest and DNA repair - It allows DNA repair to occur before entering the S phase of the cell cycle (DNA synthesis) - Failure to reapir = apoptotic cell death

Question 33

Proteotoxic response / Heat shock response:

Answer 33

: Triggered by an accumulation of unfolded, denatured, aggregated proteins. - transcription factor HSF1 activates transcription of chaperone protein HSP1 (heat shock protein)

Question 34

HSP1 function:

Answer 34

- refold denatured proteins - target damaged proteins for destruction - prevent protein aggregation (cytotoxic).

Question 35

Hypoxia response:

Answer 35

: Low O2 sensed by transcription factor HIFa - It induces proteins active in glycolysis, erthrocyte production, BV development --> to increase O2

Question 36

Antioxidant response

Answer 36

: is triggered through detection of oxidative stress and ROS to upregulate antioxidant enzymes to rebalance redox homeostasis.

Question 37

Unfolded protein response

Answer 37

: triggered by unfolded, denatured proteins in the ER - Induces production of more chaperones to enhance protein-re-folding capacity and target damaged proteins for destruction/export - Induces ER-associated protein degradation (ERAD) Promotes autophagy (self-eating breakdown of cellular components) to eliminate aggregated proteins