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Damage Tolerance
  • Function
    • can allow DNA replication to continue despite presence of DNA damage (e.g. thymidine dimer)
  • Process
    • DNA polymerase stalls at dimer
    • sliding clamp releases regular DNA polymerase and binds the one of two translesion polymerases
      • error free
        • recognizes that the dimer is normally a thymidine and the polymerase adds an adenosine opposite and continues replication
      • error prone
        • polymerase adds any base opposite the lesion and continues replication
Mismatch Repair
  • Process 
    • repairs G/T or A/C pairing
      • sometimes misincorporated due to tautomerization of the nucleotide
    • involves MutS, MutH, MutL enzymes
    • strand specific
      • recognizes which is the new strand because it is unmethylated and the old strand is methylated
  • Deficiency
    • hereditary nonpolyposis colorectal cancer 
      • aka Lynch syndrome
      • cause
        • hereditary absence of one copy of enzyme hMLH1 or hMSH2
          • second copy lost due to somatic mutation
            • known as the two-hit model
            • common to many DNA repair deficiencies
      • presentation
        • microsatellite instability
          • di-, tri-, tetranucleotide repeats that can be amplified
            • constant in number in normal cells
          • diagnostic in Lynch syndrome
        • ↑↑ risk of colorectal cancer
          • NOT preceded by benign polyps
Base Excision Repair
  • Function
    • specific endonucleases (glycosylasse) remove bases that have been modified by several common mechanisms of damage
      • e.g. deaminated cytosines (C → U) removed by uracil glycosylase
    • can take place anytime during the cell cycle but occurs primarily in G1
  • Process
    • glycosylase specific for the damaged nucleotide removed damaged base by breaking glycosidic bond
    • damaged base removed
      • sugar remains but base removed
      • creates an apurinic/apyrimidinic (AP) site
    • gap filled by DNA polymerase
    • ligation of strand nick by DNA ligase III
Nucleotide Excision Repair
  • Function 
    • removes thymidine dimers caused by UV-B light
    • removes damaged bases caused by chemicals
  • Process 
    • maintenance repair
      • XPC recognises DNA lesion and recruits XPA
      • XPB-G binds DNA and removes a chunk spanning the damaged segment
      • DNA polymerase fills the gap
      • DNA ligase seals the nick
    • transcription-coupled repair
      • RNA polymerase stalls at DNA lesion
      • CSB and XPG recognize stalled RNA polymerase
      • CSA joins complex and removes damaged site and allows transcription to continue
  • Deficiency
    • xeroderma pigmentosum (XP)
      • cause
        • lack any enzyme XPA - XPG
      • presentation
        • cannot repair UV damage
          • sunlight sensitivity
          • ↑↑↑ prevalence of skin cancer
          • corneal ulcers
      • diagnosis
        • measurement of repair mechanisms in white blood cells
      • treatment
        • avoidance of sunlight
    • Cockayne syndrome
      • cause
        • lack of CSA or CSB
      • AR
      • presentation
        • growth failure
        • photosensitivity
        • nervous system abnormalities
        • can affect any organ system
Homologous Recombination
  • Function
    • repair double-strand breaks
    • requires a sister chromatid to use as a template
      • therefore must occur after S phase of cell cycle
  • Process
    • double-strand break recognized by MRN complex
    • BRCA and BLM enzymes involved in end processing
    • Holliday junctions are formed
      • cross-shaped structures that mediate strand rejoining
    • junctions are resolved
      • may result in loss of heterozygosity
      • due to the use of the opposite strand as a template
  • Deficiency
    • Bloom syndrome
      • cause
        • lack of BLM helicase enzyme
      • presentation
        • short stature
        • rash from sun exposure
        • café-au-lait spot
        • leukemias, lymphomas, carcinomas
    • BRCA-1 involved in
      • breast, prostate, ovarian cancer
    • BRCA-2 involved in
      • breast cancer
Non-Homologous End Joining
  • Function
    • repair double-strand breaks
      • these breaks may be caused by ionizing radiation or oxidative free radicals
      • mechanism of cancer radiation therapy 
    • occurs when a sister chromatid is not available to use as a template (prior to S phase of cell cycle)
  • Process
    • break recognized by MRN complex
    • additional enzymes (Artemis, XLF, Pol μ) cut ends so they can bind
    • DNA ligase IV joins ends together
  • Deficiency
    • severe combined immunodeficiency disease (SCID)
      • one of many causes

References

 

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