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Immunology Block > DNA Damage & Repair > Flashcards

DNA Damage & Repair Flashcards

1
Q

What are the two forms of double strand break (DSB) repair?

A
  • Homologous Recombination (HR)- meiotic or mitotic
  • End Joining (NHEJ)- non homologous
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2
Q

What is AICDA?

A
  • Activation-induced cytidine deaminase, catalyzes the deamination of cytidines in DNA to uracil.
  • Clusters of deaminated cytidines are seen as damage by BER and MMR, chromosome breaks
  • Repaired by NHEJ
  • Triggers class switching and affinity maturation in B cells
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3
Q

What are the 2 main radiation forms of DNA damage?

A
  1. UV Radiation- photoactivates nucleotides and induces covalent bonds (pyrimidines), causes kinks in DNA
  2. Ionizing Radiation- usually medical sources (X-ray or gamma) through radiolysis of water (ROS), causes strand breaks
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4
Q

What are the general steps of the maturation of the Humoral (B cell) response?

A
  1. Ig antigen and activation
  2. Proliferation (clonal expansion)
  3. Maturation into 4 types:
    • Antibody secretion (plasma cell)
    • Isotype Switch
    • Affinity Maturation
    • Memory Cell
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5
Q

What are the characteristics of Nucleotide Excision Repair (NER)?

A
  • Recognizes general distortions in DNA (more flexible than BER)
  • Removes most UV photoproducts, adducts
  • Multi-protein machine removes ssDNA about 28 NT long
  • Gap is repaird by fill-in synthesis and ligation (similar to BER)
  • Usually coupled to transcription (more efficient in “non-silent” regions and template strand)
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6
Q

What are the characteristics of Mismatch Repair (MMR)?

A
  • Reverse errors made during replication (misincorporation and slippage)
  • Not obvious which strand is damaged (template not obvious)
  • Looks for discontinuity of okazaki fragments, needs to occur before gaps/nicks are sealed (coupled to replication fork)
  • Removes large chunk of ssDNA (300-500 NT)
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7
Q

What is the role of genes BRCA1 and BRCA2 in recombination?

A
  • BRCA1 promotes homologous recombination and supresses end joining
  • BRCA2 is required for early step in homologous recombination (helps broken chromosome find sister or homolog)
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8
Q

What diseases are associated with defects in VDJ recombination?

A
  • Severe Combined Immunodeficiency (SCID)- both B and T cell arms of adaptive immune response. Due to loss of RAG1 and RAG2
  • Radiosensitive+SCID (RS-SCID)- combined B/T cell immunodeficiency, cellular sensitivity to DSB (radiation). Hypomorphic mutations in NHEJ proteins.
  • Omenn’s Syndrome- autoimmune disorder (hypomorphic mutations in RAG1 and RAG2)
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9
Q

What is VDJ recombination and how does it generate receptor diversity?

A
  • Multiple versions of a coding segment (V, D, and J) are distributed at a specific locus in the chromosome.
  • One each segment (V, D, and J) is assembled into code for the variable domain of mature receptor
  • The variable domain provides specificity for different foreign agnets
  • The constant domains mediate effector functions
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10
Q

At which two points in the cell cycle does the cell check for DNA damage?

A

Before S-phase (G1) and before mitosis (G2). Will enter cause a cell cycle arrest (repaid DNA) or apoptosis (programmed cell death)

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11
Q

Which antibodies are expressed by naive B cells?

A

IgM and IgD

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12
Q

What is affinity maturation and how does it occur?

A
  • Increases the affinity or anitbody for a specific antigen (1000 fold) by altering the variable domains.
  • Involves somatic hypermutation- AICDA deaminates cytidines specifically within variable domain exons and causes base changes.
  • Cells with improved affinity survive during clonal expansion while “other” mutations die
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13
Q

What are some of the problems with AICDA function and deficiency?

A
  • The targeting of AICDA is not perfect and can cause cancer (off-target hypermutation, off-target DSB and translocations)
  • Absence of AICDA can cause immunodeficiency “hyper IgM syndrome” (failure to class switch)
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14
Q

What is adduct formation and what causes it?

A

Chemicals can promote covalen attachment to nucleotides and can interefere with replication or transcription of DNA. Often caused by carcinogens

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15
Q

What disorders are associated with defects in MMR?

A
  • Hereditary non-polyposis colon cancer (HNPCC, Lynch Syndrome)- mutation in MMR gene, usually the TGF receptor (epithilia growth)
  • Microsatellite instability can lead to other cancers and genetic diseases
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16
Q

What are 3 disorders associated with NER defects?

A
  • Xeroderma pigmentosa- UV sensitive, prone to skin cancer
  • Cockayne Syndrome and Trichothiodystrophy- developmental defects, “brittle hair syndrome”
17
Q

What are the two main types of replication errors?

A
  1. Substitutions- improved by proofreading and mismatch repair, made worse by imbalanced nucleotide pools
  2. Slippage- due to repetitive DNA and seconday structures (contracts and expands these)
18
Q

What 3 things does the cell use for genomic surveillance?

A
  1. Damage sensors- see DNA damage and activate response
  2. Transducers- usually protein kinases, activated by sensors, phosphorylate mediators
  3. Mediators- proteins that directly or indirectly activate cell cycle check points (p53) or DNA repair
19
Q

Why does the constant heavy chain domain change during isotype switching and not the light chain or variable heavy chain?

A

Because the variable domains are deteremined by VDJ and are essential for recognition. The constant domain, however, is essential for functions. So changing this domain changes the functino of the B cell, but not the type of antigen it recognizes.

20
Q

What is RAGs involvement in VDJ recombination?

A
  • RAG1 and RAG2 (only expressed in B/T cells) make a pair of DSB between signaling and coding segments.
  • The break is repaired by NHEJ, with the excised DNA circularized and then lost in subsequent cell divisions.
21
Q

What are the main excision repair systems called?

A
  • Base Excision Repair (BER)- deaminations and depurinations
  • Nucleotide Excision Repair (NER)- UV photoproducts, adducts, cross-links
  • Mismatch Repair (MMR)- replication errors
22
Q

What are the characteristics of Base Excision Repair (BER)?

A
  • DNA damage is recognized and removed by specific glycosylase (removes base, leaving AP site)
  • Single nucleotide gap is filled in by polymerase and sealed by DNA ligase
  • Least “flexible” in responding to DNA damage (due to specific glycoyslases)
23
Q

When and where does VDJ recombination occur?

A

Occurs at the DNA level and only in developing lymphocytes

24
Q

What are the general steps of VDJ recombination?

A
  1. D to J recombination (DNA)
  2. V to DJ recombination (DNA)
  3. Transcription (RNA)
  4. Translation (protein)
25
Q

What are the characteristics of non-homologous end joining (NHEJ)?

A
  • Damage at ends of DNA is removed (nuclease) and endsare made compatible (polymerase), rejoin ends with ligase
  • Usually involves a loss of squence, but it is easier and more flexible than HR
26
Q

What are the two main types of adduct formation?

A
  1. Alkylating agents- chemicals with electrophilic groups bond with electron rich atoms in DNA and adds methyl, ethyl, or larger group. Can be activated by metabolic breakdown (BPDE and smoke)
  2. Cross-linking agents- bifunctinoal agents (two reactive groups) bond two positions on DNA. Can be intrastrand or interstrand (highly toxic)
27
Q

What are the three main types of spontaneous DNA damage?

A
  1. Deamination- loss of amine group, changes A, G, or C (U, HX, or X). Results in transition mutation
  2. Base loss- rate of depurination (A/G) higher than depyrimidation (T/C), sugar/phosphate backbone left intact
  3. ROS- cleave deoxyribose sugar or phosphate backbone (strand break) or damage the base (replication block or mispair)
28
Q

How is VDJ recombination related to cancer?

A
  • Cancer can occur where translocations have happened between VDJ and cancer-causing gene, drives high expression of gene
  • Many of the Non-Hodgkin Lymphomas and some Acute Leukemias (ALL)
29
Q

Which protein induces DSB in meiosis?

A

Spo11

30
Q

What are some examples of DNA damaging chemotherapy used against cancer?

A
  • Alkylating agens (cytoxan)
  • Crosslinking agents (cis-platin)
  • Topoisomerase Inhibitors (etoposide)
31
Q

What are the characteristics of homologous recombination (HR)?

A
  • In meiosis, cells induce a DSB and recombination between homologous chromosomes generates genetic variability (gene conversion and cross-over)
  • In mitosis, the intact sister chromatid is used as template for repair (not homologous because identical)
32
Q

What is the difference in receptors for B cells vs. T cells?

A

B cells- immunoglobulins, Heavy chain (IgH) + light chaing (Igk or Ig-gamma)

T cells- T cell receptors, alpha-chain + beta-chain (alpha-beta or gamma-delta)

* Variable domains exist on each receptor so that different antigens can be seen*

33
Q

What is transletion synthesis?

A

The ability of replication forks to progress through DNA damage, error-prone and uses specialized DNA polymerase (pols eta, zeta, and mu)

34
Q

How are defects in genome surveillance involved in cancer?

A

Cancer is almost always associated with surveillance defects

  • p53 can activate cell cycle arrest or apoptosis, lost in majority of all cancers (turmor supressor)
  • BRCA1 is important for all cells, but mutated in 80% of all herediary breast cancer

Immunology Block (6 decks)

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