DNA Damage and Repair

Question 1

How do we know that many repair proteins are vital for life despite us not actually understanding them?

Answer 1

Because we never see disorders of those proteins, as they aren’t compatible with life

Question 2

What are general disorders of DNA repair against breaks called?

Answer 2

Chromosomal fragility syndromes

Question 3

Name some chromosomal fragility syndromes

Answer 3

Nijmegen breakage syndrome, fanconi anaemia, bloom syndrome.

Question 4

Chromosomal fragility syndromes all lead to…. and they are very ….?

Answer 4

All lead to early cancers, of very specific types of malignancies. All very rare though.

Question 5

The chromosome fragility syndrome Ataxia-Telangiectasia (A-T) leads to what typical cancer?

Answer 5

Non-hodgkins lymphoma

Question 6

Fanconi Anemia (FA) uses what gold standard for diagnosis?

Answer 6

Detection of cellular cross linker sensitivity

Question 7

FA has a high incidence of which cancers?

Answer 7

AML and SCC

Question 8

What inheritance can FA be?

Answer 8

AR or X-linked (23 genes can cause it)

Question 9

Most FA patients have mutations in which genes?

Answer 9

FANCA, FANCC, or FANCG

Question 10

How were some FA genes identified?

Answer 10

Fusing two cells with different mutations lead to correction of the cross linker sensitivity of the cells.. This was complementation analysis.
And some protein association studies, pull down proteins that are interacting

Question 11

The FA core complex interacts with the whole DNA damage response network including….

Answer 11

BLM, ATM, BRCA1, RAD

Question 12

Phenotype of FA can be…..

Answer 12

Quite variable

Question 13

Why do we have the FA/BRCA DNA damage pathway?

Answer 13

Aldehydes occur naturally that would be toxic without the Fanconi pathway. (This explains the overlap clinically with fetal alcohol syndrome)

Question 14

FA can cause which cancers?

Answer 14

AML, Head and neck, esophagus, vulva, and FA associated leukaemia

Question 15

What specific chromosomal changes appear in FA associated leukaemia? And how significant are they?

Answer 15

3q gain. Need to get on the bone marrow transplant list ASAP. Poor prognosis.
Inv16, t(8:21) have good survival of 73%.

Question 16

What is gene responsible for FA in the 3q gain FA assocaited leukaemia?

Answer 16

EVI1 on 3q26

Question 17

How do you test FA children for leukaemia 3q changes?

Answer 17

FISH

Question 18

What are the roles of EVI1?

Answer 18

TF in haematopoiesis and development. For lineage commitment. Role in CNS development.

Question 19

Head and neck sqaumous cell carcinomas are seen in FA, but usually seen in who?

Answer 19

Older people due to tobacco, alcohol or HPV

Question 20

BRCA2 mutations can have a lifetime risk of what?

Answer 20

85% for breast cancer. If two copies mutated then malignancy in first 10 years is 90% risk.

Question 21

The IVS7 mutation in BRCA2 that deletes 115bp of cDNA and a frameshift leads to which FA cancer typically?

Answer 21

AML

Question 22

How have some people been born with two mutated BRCA2 copies?

Answer 22

Alternative transcripts operating at different times of development. Some some transcripts functioning OK in first years.