Tumour supressor genes

Question 1

What are Tumour suppressor genes?

Answer 1

TSG encode proteins that maintain checkpoints and control genome stability
They inhibit replication and proliferation of damaged cells by:
Repairing DNA damage
Apoptosis

Question 2

Knudson’s two-hit hypothesis

Answer 2

Development of retinoblastoma requires 2 mutations… loss of both of the functional copies of tumour susceptibility gene

Most of loss-of-function mutations in tumour suppressor genes are recessive in nature. One normal allele is sufficient for cellular control
Second hit affecting normal allele is needed to disrupt gene’s function

Question 3

How do heritable cancers develop?

Answer 3

Due to an additional loss of the normal functional allele.

Question 4

List the functions of tumour suppressor genes

Answer 4

DNA repair
Induce apoptosis
Block proliferation
Oncogenes antagonist

Question 5

What causes double strand breaks?

Answer 5

Radiation and chemotherapy

Question 6

What causes single strand breaks?

Answer 6

X-rays and free radicals

Question 7

State the role of BRCA1,2

Answer 7

repair DNA double strand breaks

Question 8

Mutations of BRCA1,2 can lead to what?

Answer 8

Breast cancer, ovarian, prostate cancer etc.

Question 9

What are the treatment options for mutations in BRCA1,2?

Answer 9

PARP inhibitors

Synthetic lethality, by blocking the function of PARP proteins BRCA mutated cells die.

Question 10

Examples of PARP inhibitors

Its MOA

Answer 10

Olaparib
Niraparib
Rucaparib
(-arib)

MOA: Block the cathartic action of PARP 1 (which reverses single strand breaks)
Leads to accumulation of single strand breaks = double strand breaks = activation of cell death

Question 11

What are PARP proteins?

Answer 11

They fix single strand breaks

repair gene

Question 12

What is TP53?

P53?

Answer 12

Gene producing tumour protein 53
Acts as a tumour suppressor by regulating cellular division

It detects DNA damage
Can induce G2 cell cycle arrest -> can induce apoptosis (if repair is not possible)

P53 is in the nucleus of cells & binds directly to the DNA (as transcription factor)

Question 13

Explain the P53 negative feedback loop

Answer 13

In normal cells P53 levels are low and highly regulated

The main regulator of P53 is MDM2

Phosphorylation of P53 protein disrupts P53 MDM2 complex 
Then P53 becomes active
MDM2 regulates P53 function 
P53 regulates MDM2 transcription 
= -ve feedback loop

Question 14

Potential treatment to restore wild-type p53 function

Answer 14

MIRA-1, PRIMA-1

Question 15

Retinoblastoma protein

Answer 15

A tumor suppressor protein

RB1

prevents cell growth by inhibiting cell cycle until ready to divide
via G1 phase

Question 16

RB1 is responsible for what mutation?

Answer 16

Rare eye tumour

RB1 defective copy inherited + 2nd sporadic mutation = retinoblastoma

Question 17

What are the 2 forms of retinoblastoma?

Answer 17

Sporadic

Familial

Question 18

Give examples of how a second hit is developed in retinoblastoma

Answer 18

1- mutation/ gene deletion
2-loss of heterozygosity
3-Promoter hypermethylation

Question 19

Give an example of a familial cancer syndrome caused by inherited mutations in TSG

Answer 19

Li-Fraumeni syndrome

Question 20

List examples of TSG

Answer 20

DNA repair genes: BRCA1/2
TP53
RB1