DNA Repair

Single strand

  • Nucleotide excision repair
    • Specific endonucleases release the oligonucleotides containing damaged bases; DNA polymerase and ligase fill and reseal the gap, respectively.
    • Repairs bulky helix-distorting lesions.
    • Occurs in G1 phase of cell cycle.
    • Defective in xeroderma pigmentosum (inability to repair DNA pyrimidine-pyrimidine dimers caused by [non-ionizing] UV exposure). Findings: dry skin, extreme light sensitivity, skin cancer.
  • Base excision repair
    • Base-specific Glycosylase removes altered base and creates AP site (apurinic/apyrimidinic). One or more nucleotides are removed by AP-Endonuclease, which cleaves the 5′ end. Lyase cleaves the 3′ end. DNA Polymerase-β fills the gap and DNA Ligase seals it. Occurs throughout cell cycle.
    • Important in repair of spontaneous/toxic deamination, depurination, alkylation, oxidation.
    • Excess dietary nitrites can promote deamination of cytosine, adenine, guanine to form uracil, hypoxanthine and xanthine respectively.
    • “GEL PLease”
  • Mismatch repair
    • Guided by hypermethylation of parent strand, which helps identify the non-mutated strand for use as a template. Newly synthesized strand is recognized, mismatched nucleotides are removed, and the gap is filled and resealed. Occurs predominantly in S phase of cell cycle.
    • Defective in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]).

Double strand

  • Nonhomologous end joining
    • Brings together 2 ends of DNA fragments to repair double-stranded breaks. No requirement for homology. Some DNA may be lost.
    • Defective in ataxia telangiectasia and Fanconi anemia.
  • Homologous recombination
    • Requires two homologous DNA duplexes. A strand from the damaged dsDNA is repaired using a complementary strand from the intact homologous dsDNA as a template. Restores duplexes accurately without loss of nucleotides.
    • Defective in breast/ovarian cancers with BRCA1 mutation.
    • Bloom syndrome – generalized chromosomal instability with increased susceptibility to neoplasms due to increased crossing-over between homologous chromosomes. Dysfunctional DNA helicase encoded by BLM gene leading. Growth retardation, facial anomalies (microcephaly), photosensitive rash, immunodeficiency (recurrent infections).

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