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BIOCHEMISTRY 2 > Qiao2-3-Repair,Recombination > Flashcards

Qiao2-3-Repair,Recombination Flashcards

1
Q

What are the sources of DNA damage?

A
  1. Mistakes during replication
  2. Spontaneous mutation
  3. Induced mutations caused by environmental agents
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2
Q

What are some spontaneous DNA damage mechanisms?

A

1- Base loss/depurination: thousands of purines lost/day bc N-glycosyl linkage to deoxyribose is hydrolyzed -> AP (apurine/apyrimidine) site

2- Deamination of bases: deamination of cytosine to uracyl at ~100 bases/cell/day leads to C to T transition mutation. Also, conversion of adenine to hypoxanthine, and guanine to xanthine

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3
Q

What occurs with deaminations?

A
  • Spontaneous, pH and temp. dependent
  • May lead to mutations C->U, so will lead to C->T transition in next round of replication bc uracyl acts as thymine & pairs w/ adenine
  • Nitrous acid (HNO2) formed from nitrites in preserved meats react w/ stomach acid causing oxidative deamination
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4
Q

What is oxidative DNA damage?

A
  • Caused by ROS produced during mitochondria respiration & peroxide radicals
  • ROS introduces ~20K lesions/cell/day
  • Spontaneous modifications: hydrolytic attack, oxidative damage, uncontrolled methylation by SAM
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5
Q

What are the types of UV radiation?

A

UV-C (180-290nm): germicidal, most energetic & lethal. Absorbed by ozone layer

UV-B (290-320nm): major lethal/mutagenic fraction of sunlight

UV-A (320nm-visible): near UV, deleterious effects (bc it creates O-radicals), but it produces very few pyrimidine dimers

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6
Q

What are the consequences of UV-damage?

A
  • Adjacent pyrimidines covalently link through formation of a 4-member ring structure (CPD or thymine dimer)
  • Dimers will form between any 2 neighboring pyrimidine bases; helix bends 7-9o
  • Pyrimidine 6-4 Pyrimidone photoproducts (6-4PPs); helix bends 44o
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7
Q

What are some occupational exposures and their consequences?

A

-Diet high in salt & nitrate: stomach, esophagus

  • Diet high in fat, low in fiber, fried foods: bowel, pancreas, prostate, breast
  • Tobacco & alcohol: mouth, throat, lung, kidney, bladder
  • Asbestos: mesothelioma (damage to mesothelial cells in lining of chest & abdominal cavities)
  • Cigarette smoking: polycyclic aromatic HCs lead to G->T transversions in p53 tumor suppressor gene -> delayed lung cancer.
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8
Q

What are some carcinogens and their effects?

A

1) Arsenic: skin carcinoma, bladder cancer
2) Asbestos: mesothelioma
3) Benzene: acute leukemias
4) Radium: osteocarcinoma
5) Vinyl Chloride: liver angiosarcoma

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9
Q

What is the Ames test?

A

Test to determine the potential carcinogenic effects of chemicals:

1- Potential mutagen + histidine-dependent salmonella + homogenized liver extract are plated in agar w/o histidine

2- Incubation at 37C for 2 days 3- Count colonies of histidine-independent bacteria (these are the mutants)

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10
Q

What are some anticancer compounds that damage DNA?

A

Cisplatin, carboplatin, daunorubiicn, doxorubicin, oxaliplatin, and picoplatin

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11
Q

What are some cellular responses to DNA damage?

A

1- Checkpoint activation: signal transduction, transcriptional regulation, cell cycle arrest

2- DNA damage repair: excision repair, recombination prepair

3- Apoptosis

4- DNA damage tolerance: bypass polymerase

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12
Q

What are the 3 major types of DNA repair?

A

1- Direct reversal of damage (photolyase, AGT)

2- Excision repair (MMR, BER, NER)

3- Recombinatorial repair (DBS-repair)

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13
Q

What is direct reversal of damage?

A

A) Photolyase: reverses UV-induced damage in E.coli, plants, & some animals. Binds T-dimers & 6-4PP, absorbs a blue-light photon, & splits the photoproduct. Not in humans.

B) AGT (I-2 O6-akyltransferase, or MGMT): transfers the methyl group to a cysteine in the enzyme irreversibly (not in plants & S.pombe)

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14
Q

What are the types of excision repair?

A

A) Mismatch repair (MMR)

B) Base excision repair (BER): fixes deamination

C) Nucleotide excision repair (NER*): removes bulky adducts -UV damage

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15
Q

What is HNPCC?

A

-Hereditary nonpolyposis colorectal cancer (Lynch syndrome). Increases risk for colon cancer

  • Associated w_/Mut proteins_ from mismatch repair
  • 5% of colon cancers are the result of mutations in mismatch repair
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16
Q

What is the effect of O6-methyl-Guanine (nucleotide analog)?

A
  • It leads to cell arrest & apoptosis
  • MMR sees it as a pair mismatch, causing futile cycles of nt removal/synthesis causing breaks
  • If there is a high level of AGT, O6-meG can be quickly removed
  • Highly mutagenic
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17
Q

What is the mechanism of mismatch repair, MMR?

A

1) Mut proteins recognize mismatch
2) Identify methylated (parental) strand, and cleaves daughter strand
3) Segment is then filled by polymerase, & ligase joins to original strand.

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18
Q

What is the mechanism of base excision repair, BER ?

A

1) Deamination is identified (C-> U)
2) DNA-N-glycosylase generates AP site by hydrolysis of N-glycosidic bonds & removes base
3) Apyrimidinic (AP) endonuclease nicks the backbone at 5’ side of AP site generating a 3’-OH terminus
4) Cleavage of deoxyribose by lyase activity
5) DNA Pol/ ligase fill in and seal it.

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19
Q

What is the mechanism of photolyase?

A

1) Enzyme recognizes & binds to damage
2) light absorption by chromophore converts it to excited state
3) chromophore donates an electron to the cyclobutyl dimer
4) dimer is destabilized -> result in monomeric pyrimidines

20
Q

How can a defect in BER lead to cancer?

A
  • Mutation in DNA N-glycosylase MutY leads to APC mutation and colon cancer
  • It normally recognizes 8-OXO-G–A mispair.
21
Q

What is the mechanism of nucleotide excision repair, NER?

A

*Critical for repair of UV damage

  1. Damage recognition based on disrupted pairing by XPC or CSB/CSA-RNA pol holoenzyme
  2. Recruitment of proteins (TFIIH, XPG, XPA, XPB) to assemble repair complexes
  3. Double incisions remove 24-32 nt by XPG & XPF
  4. Excision of damage-containing nt’s
  5. Filling in and ligation
22
Q

What is Xeroderma Pigmentosum?

A
  • Deficient NER nucleotide excision repair disorder
  • Severe light sensitivity
  • Severe pigmentation irregularities
  • Frequent neurological defects
  • Early onset of skin cancer at high incidence & other cancers
23
Q

What diseasess are NER defecs linked to?

A
  • Xeroderma Pigmentosum
  • Cockayne’s syndrome (CSA/CSB)
  • Trichothiodystrophy (XPB and XPD)
24
Q

What is Cockayne’s syndrome?

A
  • Premature aging of some tissues, dwarfism, facial and limb abnormalities, neuronal abnormalities
  • Carry mutations in genes involved in or related to NER (XPB, XPD, XPG)
25
What is Trichothiodystrophy?
* Premature aging of some tissues, brittle hair, facial abnormalities, short stature, some light sensitivity * Mutations in genes involved in or related to NER (XPB, XPD)
26
What is Recombinatorial repair, DBS (3)?
* Mechanism to repair ds-breaks caused by: IR, ROS, meiosis, VDJ recombination * _A) Homologous recombination (HR):_ between sequences that are nearly identical * _B) Non-homologous end-joining (NHEJ) // Site Specific_: between sequences with a limited stretch of similarity; involves specific sites.
27
What is homologous recombination repair, HR ?
1) Enzyme recognizes break 2) End processing produces two ends; generation of ssDNA 3) Strand invasion -holiday junction formation -branch migration 4) Resolution of intermediates 5) ligation \*Use undamaged sister chromatids as template
28
What is Site-specific / Non-homologous end-joining, NHEJ?
* Moves specialized specialized sequences called mobile genetic elements (contains transposase) between non-homologous sites * Gene order can be altered, & new info added * Ex. Mating type switch in yeast & VDJ recombination for Ig diversity * **STEPS: ** ** 1)** Ku heterodimer binds to DNA ends, **2)** DNA-activated kinase recruited**, 3)** DNA ends are processed, **4)** Ligase 4 joins the ends
29
How can DNA repair pathways be exploited for cancer therapy?
There are different repair pathways, but tumor cells tend to have a preferred pathway. If a drug then inhibits such pathway, cancer cells cannot be repaired and die. Normal cells have other repair pathways, so they can continue to live.
30
What are the eukaryotic homologous recombination proteins?
**-Initiation:** end processing (Mre11/Rad50/ NBS1(XRS2)/RPA (ssDNAbp), **-Pre-synapsis:** RPA, Rad51 (strand exchange), Ras 52/54/59, BRCA 1/2 **-Heteroduplex extension:** Rad51, Pol&, PolE **-Resolution:** BLM helicase, Top3, Mus81 (endonuclease), EME1, XRCC3, Lig 1 -There might be crossing over
31
What is meiotic recombination (HR) & what is the pathway?
The exchange of genetic materials between parents before giving it to the progeny: 1- Two homologous chromosomes are paired 2- One chromosome is cut 3- Exonuclease exposes ss 3'-end 4- Strand invasion joins chromosomes
32
What are the DNA damage checkpoints actvated upon DNA damage?
**-Block entry into S-phase** through p53, Chk2, Cdc25 - **Slow DNA replication** by inhibiting late origin firing through ATR - **Block entry into M phase** through ATR & Chk1
33
How does checkpoint activation work?
1) Sensor proteins recognize damage (ATR-protein kinase, Rad17, ATM, Hus 1, ATRIP, etc.) 2) Mediators (protein complex assembly: BRCA1, Claspin, MDC1) signal to transducers 3) Chk1/2 transducers signal to effectors 4) Effector, p53 and Cdc25 phosphatase, down-regulate the cell cycle.
34
What is the biological significance of recombination?
- Generate genetic diversity - Repair of DNA breaks - Recombinational bypass of bulky DNA adducts - For chromosomal pairing during meiosis
35
What happens when p53 is activated?
**-p53 is acticvated b**y: hyperproliferative signals, DNA damage, telomere shortening, hypoxia -Active p53 leads to **cell cycle arrest, senescence, or apoptosis**
36
What are some examples of DNA damaging agents and their repair mechanism?
\*BER: X-rays, O-radicals, alkylating agents, spontaneous reactions \*NER: UV light, polycyclic aromatic HCs \*MMR: replication errors \*HR/EJ: x-rays, anti-tumor agents
37
What are some examples of DNA damage mechanisms?
- Point mutations - Transition & transversions - Insertions & deletions - Expansion & contraction of microsatellite repeats - Chromosome rearrangements (translocations, inversions, deletions)
38
What are microsatellites?
* Tandem repeats composed of subunits, 1-6 nucleotides * Account for 3% of human genome * During replication, they change in length at a rapid rate * Polymorphic, so they are used for parentage & forensic analysis * Expansion in protein coding or 5' UTRs can cause diseases (HD, FXS)
39
What are the DNA mutations and their effects on polypeptide?
- Missense: AA substitution - Neutral: change involved similar aa, no effect in function - Silent: different codon, but same aa - Nonsense: premature stop codon - Frame shift: functional effects
40
What are some inherited syndromes associated with defects in DNA repair?
_-Bloom syndrom_e (cancer, stunted growth): accessory DNA helicase for replication - _46 BR patient_ (hypersensitivity to DNA-damaging agents): *DNA ligase I* - _Werner syndrome:_ DNA helicase & 3'-exonuclease,
41
What is Ataxia Telangiectasia?
* Neurodegenerative & cancer-prone disorder * Progressive ataxia * Tumors of lymphoid origin, T-cell leukemias; impaired lymphocyte proliferation * Defective DBS response bc _mutation in ATM_, which interferes with NHEJ
42
What is FANCD1?
* Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome * Can cause aplastic anemia, GI problems, thumb and radial abnormalities, acute myeloid leukemia, short stature, mycrocephaly, head & neck, breast, ovarian, or prostate cancer * Due to hypomorphic mutation in _BRCA2_ & other genes, which i_nterferes with HR_
43
What is ATR-Seckel syndrome?
* Microcephalic dwarfism, developmental delay, dental malocclusion * Due to hypomorphic mutation in _ATR gene, which impairs DBS repair_
44
What disorders are similar to AT caused by different gene mutations?
* **ATLD**: hypomorphic mutation in MRE11 * **NBS:** mutation in NBS1 * **FA:** mutation BRCA2 & other genes
45
What is RS-SCID & Lig4 syndrome?
* Problems with VDJ recombination * **RS-SCID: null-**\> severe combined immunodeficiency. Hypomorphic -\>partial B/T cell deficiency. Due to a mutation in *_Artemis gene_* * **Lig 4:** due to hypomorphic mutation in *_LIG4 gene._* Pancytopenia or combined immunodeficiency, developmental delay, lymphoid tumors, psoriasis, diabetes II, atypical bone maturation

BIOCHEMISTRY 2 (12 decks)

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