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Radiation Biology > Hall 2 - Molecular Mechanisms of DNA & Chromosome Damage & Repair > Flashcards

Hall 2 - Molecular Mechanisms of DNA & Chromosome Damage & Repair Flashcards

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1
Q

How many DSBs after 1 Gy?

A

40

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2
Q

How many SSBs after 1 Gy?

A

1000

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3
Q

How many bases damaged after 1 Gy?

A

> 2000

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4
Q

How many DNA-DNA crosslinks after 1 Gy?

A

30

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5
Q

What type of damage predominates in cell killing?

A

Double strand breaks

Creates chromosomal aberrations that are problematic at mitosis

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6
Q

What is the energy of a spur?

A

<100 eV

~3 ion pairs
4nm diameter
Most common for photons

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7
Q

What is the energy of a blob?

A

100-500 eV

~12 ion pairs
7nm diameter
Densely ionizing radiation

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8
Q

What is the energy of a short track?

A

500-5000 eV

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9
Q

What happens when spurs and blobs cluster/ multiple sites are damaged in the same area?

A

Locally multiply damaged site

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10
Q

What is used to lyse cells and run the DNA on an agarose gel to separate according to size?

A

Pulsed-field gel electrophoresis (PFGE)

Fraction of DNA released is directly proportional to dose

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11
Q

What is used to lyse cells and see how much damaged DNA migrates (as fragments)?

A

Single-cell electrophoresis (comet assay)

Offers single-cell resolution

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12
Q

What type of lysis buffer assays for DSBs?

A

Neutral

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13
Q

What type of lysis buffer assays for SSBs?

A

Alkaline

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14
Q

What is an antibody that can be used to detect foci that contain signaling/repair proteins (DNA damage-induced nuclear foci) for DSBs?

A

gamma-H2AX
(Ab to phosphorylated H2AX)

or

53BP1
(only found at damaged loci)

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15
Q

What phosphorylates H2AX? When?

A

ATM

After DSBs

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16
Q

What can be used to measure radiosensitivity 24 hours after RT?

A

Amount of gamma-H2AX

Reflects extent of repair (detects H2AX phosphorylated by ATM after DSB, so high levels mean poor repair)

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17
Q

What repair mechanism is used when there is an incorrect base in the DNA?

A

Base excision repair

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18
Q

What initially binds to the site of a single strand break?

A

PARP and XRCC1

Remaining process is like BER

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19
Q

What removes bulky adducts in DNA?

A

Nucleotide excision repair

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20
Q

What is the damage recognition complex in NER?

A

XPC/XPE in non-transcribed region (global)
CSA/CSB in transcribed region

*Any protein starting with “XP” is named for its involvement in xeroderma pigmentosum

**CSA/B = Cockayne syndrome

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21
Q

What senses mismatch repair?

A

MSH2/6 or MSH2/3 complex

Recruits MLH1, PMS1/2, MLH3

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22
Q

What type of DNA double-strand break repair is error free? When does it occur in the cell cycle?

A

Homologous recombination

Requires an undamaged DNA strand (sister chromatid) to serve as template

Error-free

Occurs in late S and G2 phase ONLY

23
Q

What type of DNA double-strand break repair occurs in G1?

A

Non-homologous end-joining

Error-prone because no sequence homology

24
Q

What is the primary responder and orchestrator of DSBs?

A

ATM

For both HR and NHEJ:
ATM/MRN complex (Mre11/Rad50/Nbs1) binds initially

25
Q

What regulates HR vs NHEJ?

A

P53BP1

Inhibits HR

26
Q

After ATM/MRN complex binds in NHEJ, what proteins are recruited?

A

Ku70/Ku80 heterodimer

NHEJ:
ATM/MRN&raquo_space; Ku70/Ku80
» recruits DNA-PKcs
» end processing by Artemis
» repair synthesis and ligation by XRCC4

27
Q

What does the end processing in NHEJ?

A

Artemis
(endonuclease)

NHEJ:
ATM/MRN&raquo_space; Ku70/Ku80
» recruits DNA-PKcs
» end processing by Artemis
» repair synthesis and ligation by XRCC4

28
Q

What ligates at the end of NHEJ?

A

XRCC4

NHEJ:
ATM/MRN&raquo_space; Ku70/Ku80
» recruits DNA-PKcs
» end processing by Artemis
» repair synthesis and ligation by XRCC4

29
Q

After ATM/MRN complex binds in HR, what proteins are recruited?

A

RPA and BRCA1/2

HR:
ATM/MRN&raquo_space; RPA and BRCA1/2
» loads RAD51 onto RPA (RAD52 protects from degradation)
» strand invasion
» Holliday junction
» resolved via crossover or non-crossover

30
Q

What catalyzes strand invasion in HR?

A

RAD51

HR:
ATM/MRN&raquo_space; RPA and BRCA1/2
» loads RAD51 onto RPA (RAD52 protects from degradation)
» strand invasion
» Holliday junction
» resolved via crossover or non-crossover

31
Q

What happens when HR is dysregulated?

A

Loss of heterozygosity (LOH)
» cancer

32
Q

What recognizes interstrand crosslink repair complexes in S phase?

A

Fanconi anemia complex

Recognizes replication fork stalling
Excises and repairs with HR and NER

33
Q

What pathology leads to hypersensitivity to crosslinking agents?

A

Fanconi anemia

Resulting abberations = quadriradials

Cells with defects in NER or HR are moderately sensitive

34
Q

What type of damage is caused by UV light and how is it repaired?

A

Pyrimidine dimers, 6-4 photoproducts

NER

35
Q

What type of damage is caused by ionizing RT and how is it repaired?

A

DSBs, SSBs, base damage, DNA-histone crosslinks

DSB repair (HR, NHEJ), BER

36
Q

What do BER defects lead to?

A

Increased mutation rate (not radiosensitivity)

37
Q

What do NER defects lead to?

A

Increased sensitivity to UV light (XP) and chemo that creates bulky adducts (alkylating agents)

Does not increase radiosensitivity

38
Q

What do DSB repair defects lead to?

A

Increased radiosensitivity

NHEJ > HR

NHEJ defects also causes immunodeficiency due to impaired VDJ recombination

39
Q

What do defects in MSH, MLH, or PMS proteins lead to?

A

HNPCC/Lynch syndrome

40
Q

What happens in prophase?

A

Chromatin condensation, centromere visible

41
Q

What happens in metaphase?

A

Spindle formation and chromosome alignment in center

42
Q

What happens in anaphase?

A

Chromosomes move to poles

43
Q

What happens in telophase?

A

Daughter cells pull apart, chromosomes uncoil, nuclear membrane reappears

44
Q

When do chromosome aberrations happen?

A

Before duplication (G1)

Duplicated&raquo_space; identical aberrations in both sister chromatids

45
Q

When do chromatid aberrations happen?

A

After duplication (late S, G2)

Only one sister chromatid injured

46
Q

What are three lethal aberrations?

A

Dicentrics (pre-replication)
Ring (pre-replication)
Anaphase bridge (post-replication)

Require two chromosome DSBs

47
Q

What are two non-lethal aberrations?

A

Symmetric translocation (pre-replication)
Small interstitial deletion

48
Q

Why are micronuclei prognostic of cell death?

A

Pseudo-nuclear membranes that envelope DNA lacking a centromere (acentric fragments)&raquo_space; loss of genetic material at next mitosis

49
Q

What pathway do micronuclei activate?

A

cGAS-STING

> > INF-beta
infiltration of tumor by CD8+ T cells

50
Q

What causes the linear part of the cell killing curve?

A

Single charged particle track creates two chromosome DSBs (low doses)

*Terminal deletions result from one DSB, therefore also linear function of dose

51
Q

What causes the quadratic part of the cell killing curve?

A

2 separate radiation tracks (high doses)

52
Q

When can chromosomal aberrations be seen?

A

During mitosis (condensed chromatin)

Exception: micronuclei (indicate acentrics, which can be detected in interphase)

53
Q

What is the lowest single dose of RT that can be detected?

A

0.25 Gy

54
Q

What is a stable vs unstable aberration?

A

Stable = translocations (last for years, persist in stem cells)

Unstable = rings/dicentrics (disappear over time, only in terminally differentiated lymphocytes)

*Lymphocytes disappear quickly at high doses

Radiation Biology (29 decks)

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