DNA-repair

DNA Damage Repair

Cellular Response to DNA Damage

  • Complex responses to types of DNA damage in prokaryotes and eukaryotes.

  • Three main repair categories:

    • Bypass the damage

    • Directly reverse the damage

    • Remove damaged sections and replace with undamaged DNA via excision or recombinational repair.

DNA Repair Systems (Table 7.2)

  • Damage Bypass:

    • Translesion DNA synthesis: DNA polymerases IV and V in E. coli; Pol 5, pol n, pol 1, pol K, and pol a in humans.

  • Damage Reversal:

    • Photoreactivation: DNA photolyase for pyrimidine dimers.

    • Removal of methyl groups: Methyltransferase for O°-methylguanine.

  • Damage Removal:

    • Base excision repair: DNA glycosylases for damaged bases.

    • Mismatch repair: MutS, MutL, MutH in E. coli; MutSa, MutLa, EXO1 in humans.

    • Nucleotide excision repair: Various proteins for bulky adducts and pyrimidine dimers in humans.

    • Double-strand break repair: RecA, RecBCD in E. coli; MRN complex, Rad51, BRCA1/2, XRCC3 in humans.

Properties of Eukaryotic DNA Polymerases (Table 11.5)

  • DNA Polymerases Functional Overview:

    • α: No proofreading, initiates DNA synthesis.

    • δ: Proofreading, lagging strand synthesis.

    • ε: Proofreading, leading strand synthesis.

    • γ: Mitochondrial replication.

    • β: Base-excision repair.

    • η, ι, ζ, κ, θ, λ, μ, ν: Various translesion synthesis and repair functions.

Lesion Bypass

  • High-fidelity DNA polymerases cannot bypass structural lesions.

  • Specialized low-fidelity DNA polymerases replace replicative polymerases for translesion synthesis (TLS), which can introduce mutations by incorporating incorrect nucleotides.

Direct Reversal of Damaged DNA

  • Enzymatic photorepair by photolyase can directly reverse pyrimidine dimers.

  • Repair through light repair (photoreactivation) is absent in placental mammals.

  • Methyltransferases repair O6-methylguanine but are consumed in the process.

Proofreading and Error Correction

  • DNA polymerase recognizes and removes incorrect nucleotides, achieving a very low error rate during DNA replication (1 in 10,000,000).

  • Proofreading enhances replication efficiency significantly.

Base and Nucleotide Excision Repair

  • Base excision repair links enzyme actions (DNA glycosylases, AP endonuclease) for damaged base removal.

  • Comprises both short patch and long patch repair pathways, involving multiple enzyme interactions to ensure accuracy in DNA repair.

Nucleotide Excision Repair

  • Essential for repairing bulky lesions, particularly those caused by UV light.

  • Defective in xeroderma pigmentosum, leading to severe sensitivity to UV exposure.

  • Involves coordinated action of multiple proteins to excise damage and restore DNA integrity.

Double-Strand Break Repair (DSB)

  • Induced by reactive oxygen species and ionizing radiation.

  • Repaired by homologous recombination or nonhomologous end joining, with the former being more precise but less frequent.

Consequences of Imperfect Repair

  • Error-prone repair mechanisms such as nonhomologous end joining may resolve immediate DNA breaks but can lead to mutations.

Overview of DNA Damage and Repair

  • Various repair mechanisms correlate with types of DNA damage, highlighting specificity in repair processes.