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Flora Ross > DNA damage and repair > Flashcards

DNA damage and repair Flashcards

1
Q

What mechanism protects cells from DNA damage?

A

Cell cycle checkpoints pause the cell cycle and give time to repair DD

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2
Q

3 examples of DNA damage

A

C>U deamination, pairs with A instead of G

Thymine bonds due to UV radiation

Single or double strand DNA breaks

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3
Q

Example of checkpoint dysregulation

A

Ataxia telangiectasia - ATM gene

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4
Q

What is the function of ATM protein?

A

Ser/thr kinase that signals DSBs in G1-S and G2-M checkpoints

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5
Q

4 clinical features of A-T

A

Cerebellar and peripheral ataxia

Immunodeficiency due to chr14 rearrangements at TCR/BCR locus

High sensitivity to ionising radiation

Increased risk of cancers (hetz carriers and homoz affected)

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6
Q

What are the function of fanconi anemia genes? Main gene?

A

Genes involves in repair of cross-linking due to UV exposure

FANCA mutated in 2/3 cases

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7
Q

3 clinical features of fanconi anemia

A

Major congenital abnormalities including absent thumbs

Pancytopenia & BMF

High risk of leukemia

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8
Q

What is the error rate of DNA replication in meiosis?

A

~1 in 1million bp per gamete

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9
Q

2 DNA replication diseases & genes

A

Hutchison-Gilford Progeria (LMNA)

Bloom syndrome (BLM)

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10
Q

What is the function of BLM?

A

Encodes RecQ helicase essential for suppressing inappropriate recombination and increasing stability

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11
Q

What abnormality is seen in Bloom syndrome cells?

A

Hyper-recombination/high level of sister chromatid exchange

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12
Q

What are the 3 Excision Repair mechanisms?

A

Base Excision Repair

Nucleotide Excision Repair

Mismatch Repair

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13
Q

Role of BER pathway

A

Removal of oxidative damage that causes small non-helix distorting lesions

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14
Q

Key enzyme for BER and function

A

DNA glycosylases recognise/remove damage, form AP sites and recruit AP endonuclease, polymerase and ligase to repair the lesion

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15
Q

1 example of BER dysfunction and gene

A

MUTYH-associated polyposis

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16
Q

Function of MUTYH

A

DNA glycosylase that excises DNA when adenine is inappropriately paired with guanine, cytosine or 8-oxyguanine

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17
Q

2 clinical features of MAP

A

Oligopolyposis (10-100 colon polyps)

43-100% lifetime risk of CRC

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18
Q

Types of MUTYH mutations

A

99% = missense = loss of glycosylase activity

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19
Q

Function of NER pathway

A

Removes thymine dimer bonds caused by UV radiation

20
Q

3 example NER genes and associated disease

A

XPC, ERCC2, POLH

Xeroderma pigmentosum

21
Q

Function of MMR pathway

A

Recognises insertions, deletions and missense arising in replication/recombination, that elude the polymerase proof-reading capacity

22
Q

4 MMR proteins and their structure

A

MSH2-MSH6 (MutS alpha)

MLH1-PMS2 (MutL alpha)

Form heterodimers and then complex together to signal site of mismatch. Guide exonuclease 1 to excise and polymerase/ligase to repair the lesion

23
Q

2 dominant MMR proteins? What happens to the other 2 MMR proteins?

A

MSH/MLH1

MSH6/PMS2 are unstable when not dimerised with their partner

24
Q

How is defective MMR associated with microsatellite instability?

A

SNV and frameshifts accumulate, especially in repeat regions e.g. microsatellites. Changes in MS lengths represent instability and is used as a marker of defective MMR

25
Q

Common cancers for Lynch syndrome patients? Genotype/phenotype correlation?

A

Colorectal (all genes)
GI (MSH2/MLH1)
Renal/bladder (MSH2/6)
Prostate (MSH2)
Breast (MLH1)

26
Q

Genes with highest risk of any cancer

A

MSH2/MLH1 = 72%

27
Q

Average age of onset of LS associated cancer?

A

45y (higher for MSH6/PMS2)

28
Q

Describe the mechanism of EPCAM deletions

A

3’ deletion of EPCAM, fuses with downstream MSH2, resulting in hypermethylation of MSH2 promoter and gene silencing

Example of a heritable epimutation

29
Q

What is the clinical difference between large and small EPCAM deletions?

A

Large (MSH2 deletion) are phenotypically same as MSH2 mutations

Small (epimutation) are associated with GI tract cancers only

30
Q

What is the testing pathway for a CRC with MSI-high result?

A

BRAFV600E - positive - no further testing (associated with sporadic CRC)

negative

MLH1 promoter hypermethylation - positive - no further testing (associated with sporadic CRC)

negative

Germline LS testing

31
Q

Why is it appropriate to test for MSI in tumors with normal IHC for all 4 MMR proteins?

A

5% of LS patients have a missense that encodes a non-functional but immunoreactive MMR protein (i.e. normal IHC stain)

32
Q

What is the function of APC in the Wnt/B-catenin pathway?

A

TS protein that forms a complex that inhibits B-catenin, inhibiting downstream transcriptional activity and cell proliferation

33
Q

When is APC commonly mutated?

A

In the colorectal adenoma to carcinoma sequence (mutated in polyps)

34
Q

1 genotype/phenotype correlation for familial adenomatous polyposis

A

PTC in the last exon escape NMD therefore express partially functional protein = attenuated (mild) FAP

35
Q

1 example of a DSB repair pathway and 2 important genes

A

Homologous Recombination

BRCA proteins localise with RAD51 to initiate HR

RAD51 is a strand exchange protein to catalyse invasion of homologous chromosome at site of damage and provide ssDNA template for repair

36
Q

What are the lifetime risks of breast and ovarian cancer in HBOC patient?

A

Breast = 38-87%

Ovarian = 16-63%

37
Q

Why is diagnosis of HBOC complex?

A

High rates of sporadic BrCa (women have 1 in 8 lifetime risk), incomplete penetrance and phenocopies

38
Q

4 examples of when HBOC may be suspected

A

Dx <50y

2 different primary breast cancers

Male breast cancers

Strong family history

39
Q

Difference between BRCA1/2 phenotypes

A

BRCA1 = commonly triple negative. Negligible risk to males

BRCA2 = more variable e.g. also pancreatic, melanoma and increased risk for male breast (9%)/prostate (20%) cancers

40
Q

Types of BRCA mutations

A

Mostly null but some missense reported

10% are large rearrangements or deletions

41
Q

1 example of a BRCA founder variant

A

Orkney Westray 1 in 100
BRCA1 c.5207T>C p.V1736A

42
Q

What is synthetic lethality?

A

Genetic interaction with combination of >2 events results in cell death. Demonstrates functional relationship between genes

43
Q

Example of synthetic lethality treatment

A

PARP inhibition for BRCA-mutant breast cancer

PARP repairs SSBs by BER. If PARP is inhibited, no SSB repair converts damage to DSBs. In the absence of BRCA, DSBs accumulate and induce apoptosis

Olaparib improves progression free survival in primary and metastatic BRCA-mutant breast cancer

44
Q

Gene implicated in Nijmegan Breakage Syndrome

A

NBN, encodes nibrin (HR protein) that has increased activity in immune cells due to VDJ recombination

45
Q

3 clinical features of Nijmegan Breakage Syndrome

A

Short stature

Dev delay

Risk of B/T cell lymphomas due to rearrangements involving IGH and TCR/BCR locus

Flora Ross (12 decks)

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