DNA repair and cancer

Question 1

Exogenous sources of DNA damage

Answer 1

Ionising radiation 
Alkylating agents 
Free radicals (from smoking, ionising radiation and UV light) 
Mutagenic chemicals 
Anti cancer drugs

Question 2

Sources of ionising radiation

Answer 2

CT 
X-ray 
Brazil nuts
radon gas from ground
Nuclear radiation

Question 3

Endogenous sources of radiation

Answer 3

Free radicals -Metabolism and inflammation both form free radicals which can cause DNA damage
and replication errors

Question 4

Types of DNA damage

Answer 4

Deamination (chemical changes in bases may change from C to U) 
Mismatches of base pairs 
Pyrimidine diner (2 Pyrimidine bases attached)
Double strand break 
Single strand break
Intercalating agent (some sort of chemical between)
bulky addict (addition of a bulky chemical) 
Cross links preventing strands from being split 

Up to a million of these errors per cell a day

Question 5

What is DNA replication stress

Answer 5

The many things that may go wrong during DNA replication because there are so many opportunities for it go badly. definition; Inefficient replication that leads to replication fork slowing, stalling and or breaking

Question 6

why do we need DNA/chromosome integrity?

Answer 6

Too many mutations will make you ill and don’t want to pass on faulty chromosomes to offspring or they will be unhealthy

Question 7

how to repair double strand break?

Answer 7

after replication use identical sister chromatid and if not gone through replication there is the other homologous chromosome which you can use to repair the break (copy the DNA sequence of these)

Question 8

how to repair single strand break?

Answer 8

using the opposite strand (unbroken)

Question 9

what causes a mutation

Answer 9

when DNA damage is not recognised or if the DNA repair mechanisms fail

Question 10

causes of replication stress

Answer 10

1) replication machinery goes wrong e.g DNA pol may misincoperate a different base. Also many proteins in process may go wrong.
2) replication fork progression is hindered by fragile sites, repetitive DNA or DNA lesions
3) defects in response pathways

Question 11

how does repetitive DNA result in replication stress?

Answer 11

can lead to fork slippage. When new DNA is made an A could loop out and then the new strand will be one base longer (backward slippage) than the other. or could happen in reverse resulting in 1 shorter base (forward slippage). This is not recognised by DNA repair mechanisms because looks normal

Question 12

What are trinucleotide repeat disorders

Answer 12

fork slippage leading to an extra codon. (3bases) e.g Huntington’s which is extra CAG.

Question 13

what is Huntington’s

Answer 13

Many more repeats in Huntington’s and this means it doesn’t fold properly and aggregates in neurones. is dominant, progressive and late onset. depending on how many repeats is how bad it is

Question 14

what does replication stress or DNA damage lead to

Answer 14

A DNA damage response. different repair mechanisms for different damage. Uses signals which are picked up sensors. passed onto transducers which activate effectors which decide what to do with mutation. (cascade)

Question 15

DNA repair mechanism result in

Answer 15

senescence(cellar rest)/apoptosis(cell death) (if levels of damage are very high)or repair of cell(proliferation).

Question 16

types of repair mechanism

Answer 16

• if something going on with base take it away and replace it (Base excision)
• something wrong with nucleotide e.g bulky addict remove and replace nucleotide (nucleotide excision)
• mismatch repair, take away and replace small strand with error
• double stranded break or both fixed together use recombinational repair to fix themselves

Question 17

describe base excision repair

Answer 17

deamination = cytosine to uracil. uracil is detected and removed and replace with complimentary base

Question 18

describe nucleotide excision repair

Answer 18

Uv damage results in thiamine dimer once this is detected the enzyme cuts out around the faulty nucleotide and DNA pol replaces the strand removed and ligase steals the backbone.

Question 19

describe non-homologous end joining for double strand break repair

Answer 19

fuse 2 broken bits of DNA together. Break is recognised, a protein removes some of the damage and DNA ligase joins them together-often results in mutation because can’t just cut random bits before joining together

Question 20

describe homologous directed repair for double strand break repair

Answer 20

use sister other homologous chromosome or sister chromatid to repair double break. Much better and no mutations but much less common method of repair. Fixed using holiday junctions

Question 21

what does mutation accumulation lead to?

Answer 21

replication stress which then causes more mutations this leads to carcinogenesis

Question 22

what is intra-tumour heterogeneity?

Answer 22

the fact that 1 tumour may contain multiple sub clones of different cells that are cancerous.

Question 23

what is the problem with intra-tumour heterogeneity?

Answer 23

When treating it with an anticancer it will initially shrink the tumour because drug is very effective against one of the sub clones. The problem then is that another sub clone is resistant to this anticancer drug and this will multiply (colonel expansion) and now there will be now way to get rid of it.

Question 24

Problem with using chemicals to treat cancer?

Answer 24

chemicals can also cause mutations which may be resistant- promotes tumour evolution

Question 25

synthetic lethality strategies

Answer 25

target the gene with the cancer mutation and the other gene remains unaffected. Example of this is PARP inhibitors. PARP inhibitor will cause lots of double strand breaks. Normal cells will be able to repair this and survive but some cancer cells with not and this will lead to death of cell.