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Updated: Oct 19 2021

DNA Repair

  • 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 (glycosylases) 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 I
        • this protein has 5' to 3' exonuclease activity
      • 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, and 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
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