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Biochemistry- Unit One
DNA Damage and Repair (T Pierce)
34
Medical
Post-Graduate
01/21/2009

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Term
Examples of alkylating agents
Definition
  • alkyl sulfate/sulfite
  • 2-napthylamine (dyes)
  • N,N dimenthylnitrosamine
  • N-methyl-N-ethylnitrosamine
  • MNNG
  • MNU
Term
Effect of methylation of guanine on DNA
Definition
this will inhibit telomere formation, preventing formation of helix (binds electron rich regions on guanine)
Term
effect of oxidative deamination of nitrogenous bases
Definition
  • cytosine coverted to uracil (uracil should not be in DNA)
  • 5-methylcytosine converted to thymine (genome that was suppose to be silenced, but is expressed)
Term
What type of regions are "hotspots" for point mutations?
Definition
GC rich regions
Term
Agents of oxidative deamination of adosine and cytosine
Definition
  • sodium nitrite (salt cured ham) when it is converted to nitrous acid in the stomach
  • sodium bisulfide (wine)
Term
Effect of UV light on DNA
Definition
  • causes formation of thymine dimers
    • disrupts base pairing, so it put kink in DNA phosphodiester backbone
    • leads to corruption of molecular symmetry and DNA protein interactions
    • cause altering of chromatine structure
Term
Examples of intercalating agents
Definition
  • ethidium bromide
  • adriamycin
  • actinomycin D
  • psoralen
Term
Effect of interacaltion on DNA structure
Definition
these agents can get in btw base stacking interactions, leading to stretching out of helix, leading to disruption of DNA backbone
Term

Clinical use and action of adriamycin/doxorubicin

Definition
  • clinical use- leukemia treatment
  • action- block DNA and RNA polymerase
Term
action of actinomycin D
Definition
  • action
    • less than 10 uM block RNA Pol.
    • more than 10 uM blocks both RNA and DNA Pol.
Term

Action of psoralen

Definition
  1. psoralen intercalate within DNA
  2. expose it to UV light
  3. cause covalent bonds to form btw DNA strands
  4. this cause DNA to be unable to denature
Term
Mechanism of Activation of benzopyrene and aflatoxin
Definition
add cytochrome p450 oxidase to form epoxide and covalently bonds with guanine, thereby acting to intercalate in between bases, thereby disrupting structure
Term
DNA damage repair mechanisms
Definition
  • direct reversal
    • photoreactivation
    • strand break repair
    • demethylase-transferase (takes methyl from where it shouldnt be and puts it where it should be)
    • apurinic site repair (fill hole)
  • exision repair- short or long patch repair
  • recombination repair
  • post-replication repair (SOS repair)
Term
Damage repair due to UV light
Definition

photoreactivation, where we will use energy from visible light to split bonds forming dimer

Term
Mechanism of strand break repair
Definition
  • single strand via ligase
  • double strand (more complex)
    • double strand rejoining
    • homologous recombination (chromosome crossing over)
Term
Process of DNA exicion repair
Definition
  1. damage recognition system
  2. damage specific endonuclease recruitment (nick DNA strand 5' of damage site
  3. 5'-3' exonucleasue activity to clear out damaged region (3 ways to do so)
    1. part of DNA polymerase I
    2. unique enzyme
    3. helicase mechanism
  4. two options
    1. 5'-3' DNA Pol. I replaces dNTP's
    2. DNA Pol. II fills gaps
  5. ligase seals strand break
  6. repair mechansim goes back to monitoring for additional changes
Term
How is recombination regulated
Definition
  • occurs between highly specific recombination sequencs in various regions of DNA
  • sequences treated like cassettes of genetic information
  • these sequences move from one genetic domain to another, controlling gene expression through chromatin reorganizing and repackaging
Term

Holliday model for homologous recombination

Definition
  1. nicks introduces at same position in both parental models
  2. nicked strands exchange by complementary base pairing and ligation
  3. this produces a cross stranded inermediate called holiday junction
Term
Mechanism of recombination when only one strand is nicked
Definition
  1. The nicked strand will displace one strand and bind to the other strand via base pairing.
  2. This loop is cleaved and will pair with first parental molecule, yielding Holliday junction.
Term
What induces SOS repair systems
Definition
extensive DNA damage during active portion of cell cycle (late G1, S, G2)
Term
Purpose of SOS repair system
Definition
fix the damage fast or cell death (if too much damage, signal for apoptosis)
Term
SOS repair response to thymine dimer
Definition
It will allow polymerase to continue its action, but it does the thymine dimer gap remains to be fixed, which can be done by polymerase and ligase.
Term
Effect of genetic predisposition to expression of SOS repair recombination system
Definition
  • leads to genetic instability
  • faulty or unprogrammed DNA recombinations
  • cancer
  • cell death
Term
Describe the mechanism of SOS repair RecA-LexA system
Definition
  1. RecA protein sense ssDNA and tightly binds to ssDNA
  2. RecA protein change confirmation upon binding and activates latent protease activity
  3. RecA protease specifically cleaves Lex A protein
    1. LexA is transcriptional silencing protein that sits on promotor elements
  4. inactivation of Lex A permit expression of previously repressed genes
    1. these genes are for DNA damage repair and stabilization genes
    2. many of these induced DNA repair systems are lower fidelity than constituitively expressed counterparts
  5. DNA damage is repaired (error prone)
  6. ssDNA signal activating RecA removed
  7. RecA reverts to original confirmation (no protease activity)
  8. LexA protein builds up and block transcription of DNA damage repair genes
Term
Mechanism of p53 (anti-oncogene)
Definition
  1. binds to ssDNA to stabilize (SSBP)
  2. leads to confirmation change in p53
  3. leads to activation of TF's that serve as DNA repair genes
    1. blocks G1/S entry
  4. but if repair system cant keep up with damage, it activates cell death system
Term
Effect of mutation on p53 structure
Definition
turns into a tetramer that is functionally inactive
Term
Structure of p53
Definition
functions as monomer (SSBP) and dimer (TF)
Term
External chemicals/agents that can activate p53
Definition
  • ionitation make ATM to activate p53
    • activate kinase which activate p53
    • directly activate p53
  • UV make ATM to activate p53
Term
p53 induces expression of what important protein?
Definition
p21
Term
Mechanism of action of p21
Definition
  1. p21 bind to cyclin dependent kinase (CDK) (as inhibitor of cell cycle)
  2. along with cyclin and CDK, form PCNA
    1. loss of DNA pol. processivity (shut down replication)
    2. switch from replication to repair mode
Term

Role of triplet repeat in disease

Definition

a certain sequence is repeated, causing expansion (makes disease worse) 

Term
Genetics and cause of Hunington disease
Definition
  • autosomal dominant neurological disorder
  • abnormal brain protein
    • CAG triplet repeats (glutatmine)
  • repeats will increase with familial generations
  • excess glutamine leads to protein aggregation and neurological dysfunction/ apoptosis
Term
Genetics and cause of fragile X syndrome
Definition
  • CGG repeat triplet sequences in FMR1 gene, which is methylation site
    • leads to chromatin condensation, which will silence FMR1 gene
      • inhibited signal transduction
      • RNA trafficking from nucleus
      • neural development
Term

Examples of faulty DNA repair mechanisms

Definition
  • Xeroderma pigmentosum- bad UV repair (eye, nerve problems, skin cancer)
  • Ataxia Telanglectasia- no strand break repair (X rays lethal, many leukemias and nerve problems, sensitive to ionizing radiation)
  • Falconi's anemia- no X link repair (hemorrhage, mental retardation, fetal Hb, infection)
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