DNA Repair and Cancer

Question 1

What kinds of damages are there to DNA? Which is worse?

Answer 1

Single stranded damage

Double stranded damage. This is worse.

Question 2

What are some exogenous sources to DNA damage?

Answer 2

Ionising radiation
Alkylating agents
Mutagenic chemicals
Anti-cancer drugs
Free radicals

Question 3

What are some endogenous sources to DNA damage?

Answer 3

Replication errors

Free radicals

Question 4

Give some types of DNA damage that can happen.

Answer 4

Apurinic site
Deamination
Mismatches
Doublestrand breaks
Intercalating agent
Single strand breaks.

Question 5

What is deamination?

Answer 5

When G pairs up with U instead of C for example. (Involving Uracil)

Question 6

What is mismatching?

Answer 6

When G pairs up with T instead of C for example.

Question 7

How can mismatching be fixed?

Answer 7

By proofreading. When a mismatch occur DNA exonuclease can come in and remove the mismatched nitrogenous base to then start again.

Question 8

Why can repetitive DNA be a problem?

Answer 8

It can lead to fork slippage. When a sequence is repeated CAGCAGCAGCAGCAG over and over again a lot of complementary nucleotides want to match it. This results in the new strand having either an extra nucleotide or one too few. (Insertion and deletion)

Question 9

What are trinucleotide repeat disorders?

Answer 9

Where fork slippage has occurred and either insertion or deletion occurred. Such disorders as Huntington’s, Spinocerebellar ataxia and Fragile X.

Question 10

Explain Huntingtons on a MCBG level.

Answer 10

A lot of CAG repeats. Insertion mutation occurs and whereas a normal gene should have 6-39 repeats the Huntington one has 35-121 repeats.
This means that the protein coded for (Huntingtin) does not fold normally and aggregates in nerves.

Question 11

Explain replication stress.

Answer 11

Inefficient replication that leads to fork slowing, stalling and/or breakage.

Question 12

What are the three outcomes in case of DNA damage in response pathways?

Answer 12

Senescence
Proliferation
Apoptosis

Question 13

What is senescence?

Answer 13

When a cell can’t divide anymore but still carry out its function.
It can pick up more mutations and more dangerous mutations in the long run.
This also causes permanent cell cycle arrest.

Question 14

What is proliferation?

Answer 14

When the cell continues to divide with its mutation.

This is actually the preferred outcome due to DNA repair.

Question 15

What is apoptosis?

Answer 15

When the cell dies instead.

Question 16

How does base excision repair work?

Answer 16

Deamination occur which converts a cytosine base into a uracil.
The uracil is detected and then removed by exonuclease leaving a base-less nucleotide.
The base-less nucleotide is removed leaving a small hole in the DNA backbone.
The hole is then filled with the right base by DNA polymerase and the gap is sealed by ligase.

Question 17

How does nucleotide excision repair work?

Answer 17

UV radiation produces a thymine dimer. This causes to thymine to link together on the same strand and creates a ‘bubble’.
When the dimer has been detected the surrounding DNA is opened to form an even larger bubble.
Exonuclease then cut the damaged region.
DNA polymerase replaces the excised DNA and ligase seals the backbone with new DNA.

Question 18

How can double strand breaks be repaired? What is most favourable?

Answer 18

By non-homologous ends joining.

By homologous ends joining. This is most favourable. Ideally it is two sister chromatids.

Question 19

Explain non-homologous ends joining.

Answer 19

DNA-PK removes damaged ends.
Ligase joins two non-homologous ends together.
This is likely to form mutations.

Question 20

What are the different steps of cancer?

Answer 20

Normal cell
Hyperproliferation
Early adenoma
Intermediate adenoma
Late adenoma
Carcinoma
Metastasis
(In between these steps several mutations need to happen.)

Question 21

What are heterogenous tumours? Why can they be extra dangerous?

Answer 21

Tumours which are not of identical cells. Because this means that some parts of the tumour might be resistant to different drugs. Meaning one drug might not work on all of the tumour.