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MT cell bio > Cancer and DNA repair- 4 lectures > Flashcards

Cancer and DNA repair- 4 lectures Flashcards

1
Q

2 types of DNA damage

A

endogenous- spontaneous damage from defective repair etc
exogenous- from radiation, sunlight etc

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2
Q

biggest mutation burden

A

SSBs- 55k per cell per day

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3
Q

example of 2 types of DNA damage which aren’t DSBs or SSBs

A

cytosine deamination
depurination/depyrimidination

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4
Q

2 ways of identifying DNA repair proteins

A

looking for abnormal karotypes in mutants
mutational signatures- tracking specific mutations in sequences (you can do a lot of mathsy stuff out of this)

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5
Q

photoylases

A

direct DNA repair enzymes. convert pyrimidine dimers into normal base pairs using photons

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6
Q

alkyltransferases

A

transfer methyl groups to cysteine- also direct DNA damage reversal

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7
Q

base excision repair (BER)- early steps

A

DNA glycosylase does the excision of a lesion
nick is then created

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8
Q

2 types of BER

A

short patch- repairs single BP gaps by cutting out the BP
long patch- several nucleotides need to be replaced- damaged DNA is a ‘flap’ which is removed

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9
Q

NER meaning

A

nucleotide excision repair

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10
Q

rough steps of NER

A

detection of unpairing and abnormal DNA structure
incisions made at both sides of a lesion
excision w helicases
DNA synthesis and ligation

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11
Q

what is transcription coupled NER

A

a version of NER which happens during transcription- triggered by RNA Pol II detecting damage
similar events to regular NER

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12
Q

what is ICL repair

A

interstrand cross-link repair

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13
Q

Falconi anaemia

A

aplastic anaemia with short stature, hypogonadism, skin pigmentation
Due to defective ICL DNA damage repair

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14
Q

examples of pathways used in ICL

A

DNA polymerase synthesis, hom. recomb. and NER- she’s diverse

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15
Q

examples of when detection occurs

A

DNA replication or transcription, or independently of other pathways

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16
Q

2 pathways for DSB repair

A

NHEJ, HR

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17
Q

difference between DSB repair paths

A

NHEJ can occur at any point in the cell cycle, more error-prone?

HR requires a sister chromatid, so is restricted to S/G2- the sister chromatid makes it more accurate

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18
Q

3 pathways of HR

A

single-strand annealing

double holliday junction (DHJ)

synthesis-dependent strand-annealing

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19
Q

single-strand annealing HR

A

3’OH generation, annealing of the homologous sequence, removal of ‘flaps’ and ligation

-often leads to deletions

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20
Q

double holliday junction pathway

A

resection, one end then ‘invades; the sister chromatin
second end captured in a D-loop, 2 HJs are formed
can lead to gene conversion of recombination, depending on how cleavage occurs
dissolution doesn’t lead to crossing over, resolution can

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21
Q

synthesis-dependent strand-annealing pathway

A

resection, invasion of sister chromatid, polymerase then fills in and completes the repair with no impact on the sister chromatid

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22
Q

strand invasion protein

A

Rad51

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23
Q

how is HR chosen over NHEJ

A

MRN displaces recruited Ku, preventing the pathway from occuring

24
Q

NHEJ

A

non-homologous end joining

25
Q

initial recruited protein for NHEJ

A

Ku70/80 dimer (i think)

26
Q

C-NHEJ

A

canonical NHEJ, evolutionarily conserved and pretty much error-free

27
Q

general steps of NHEJ

A

recognition of ends, terminal processing, synthesis and ligation

28
Q

C-NHEJ steps

A

Ku end binding

processing and damage removal- artemis (endo and exonuclease), pol u polymerases

ligation- complex w Lig4, promoted by the DNA-PKcs that binds early on

29
Q

A-NHEJ

A

alternative NHEJ, used mostly during mitosis when there aren’t a lot of other options

30
Q

A-NHEJ proteins

A

very biochemically distinct

MRN complex does resection, PARP and Lig3 involved in later steps

31
Q

why does A-NHEJ lead to deletions?

A

uses microhomology to bring together strands- but these overlap regions can be really small, hence errors

32
Q

NHEJ other role

A

important in antibody gene rearrangement (V(D)J) recombination

important in early stages of immunoglobin/TCR production- helps variability

33
Q

class switch recombination

A

changes the type of antibody being produced- IgGs to IgMs etc

34
Q

mechanism of V(D)J recombination

A

generation of DSBs by RAG proteins, processing by NHEJ leading to a join

35
Q

replicative polymerases- lowest to highest fidelity

A

pol alpha < pol beta < pol epsilon

36
Q

which polymerases are involved in proofreading?

A

polymerases epsilon and gamma

37
Q

how does proofreading work?

A

the terminus with the incorrect nucleotide flips into the exonuclease site of the polymerase- nucleotide is removed

38
Q

3 responses to misincorporation

A

dissociation- when a regular exonuclease will come and remove the nucleotide
extension- polymerase carries on regardless, potential mutation
proofreading by polymerases

39
Q

example of a common misincorporation

A

rNTP instead of dNTP, causing backbone issues as RNA is less stable and this can cause nicks to form
can also lead to stalling and fork breakage

40
Q

what is RER?

A

ribonucleotide excision repair

41
Q

rough steps of RER

A

RNAse makes an incision, extension by pol gamma, flap is cleaved and nick is ligated

42
Q

what is MMR

A

mismatch repair

43
Q

MMR steps

A

incorrectly inserted nucleotides are removed by a complex binding to the lagging strand,
proteins are recruited and identify the daughter strand,
exonuclease removes ssDNA around the mismatch,
pol gamma resynthesis,
ligation

44
Q

3 ways bypass without repair can occur

A

template switching- fork just goes past the damage
translesion synthesis polymerases are recruited- this replaces the normal polymerase, the catalytic subunit can accommodate damage better
repriming by PrimPOl- allows gap filling and repair by pol gamma

45
Q

what is break induced repair?

A

mechanism of DNA repair following a break in the replication fork which acts similarly to HR

46
Q

BIR steps

A

resection of the cut end

strand invasion

extension of D loop

lagging strand synthesis by Pol gamma

47
Q

why are stable dNTP levels important?

A

high dNTP concentration can reduce polymerase fidelity and delay entry to S phase

low dNTP concentration can lead to fork arrest, telomere and mtDNA defects, cause epigenetic breakdown, encourage rNMP incorporation

48
Q

what maintains dNTP levels?

A

regulation of proteins ribonucleotide reductase (generates dNTPs) and SAMHD1 (keeps levels low)

49
Q

example of a damage checkpoint

A

p53, a tumour suppressor, is important in the G1/S and G2/M checkpoints

50
Q

proteins needed to detect damage and encourage it to be fixed

A

sensors

transducers

effectors

51
Q

how can checkpoints be identified?

A

genetics (e.g. looking at repair mutants after causing damage, looking at conservation of proteins)

52
Q

how can a DSB lead to delay in cell cycle continuation?

A

MRN complex acts as a sensor

downstream phosphorylation of effectors- e.g. Chk2

this phosphorylation of Chk2 blocks phosphatase activity, so CDK remains phosphorylated and inactive, so no cell cycle progression

53
Q

other ways of getting G2-M blocks other than DSBs

A

replication fork stalling

low dNTPs and template damage can lead to this fork stalling

54
Q

another molecule which can trigger a block to mitotic entry

A

ATR, which eventually phosphorylates Chk1, can also help stabilise forks or stimulate dNTP synthesis, reduce origin firing (less forks becoming activated)

55
Q

what does p53 do?

A

induces apoptosis of stressed cells

cellular stress leads to p53 stabilisation, rather than its degradation, and p53 can then encourage transcription of apoptotic proteins such as PUMA and NOXA

56
Q

what kind of damages can lead to apoptosis by the p53 pathway?

A

DSBs, HR defects, telomere dysfunction

MT cell bio (6 decks)

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