12.2 DNA damage and repair mechanisms

DNA damage happens constantly, threatening our genetic integrity. Luckily, our cells have evolved clever repair mechanisms to fix these mistakes. From UV-induced dimers to oxidative damage, various processes work tirelessly to maintain our DNA.

Understanding these repair pathways is crucial for grasping how cells protect their genetic material. We'll explore the main types of DNA damage and the specialized enzymes that swoop in to save the day, keeping our genome intact.

DNA Repair Mechanisms

Excision Repair Pathways

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• Base excision repair removes and replaces damaged individual bases (oxidized or alkylated bases) using DNA glycosylase and AP endonuclease enzymes
• Nucleotide excision repair removes and replaces damaged segments of DNA containing bulky adducts or UV-induced dimers (pyrimidine dimers) using endonucleases to excise the damaged segment and DNA polymerase to fill in the gap
• Mismatch repair corrects errors made during DNA replication that result in mismatched base pairs
  • Recognizes and binds to mismatched base pairs
  • Endonuclease nicks the newly synthesized strand containing the mismatch
  • Exonuclease removes the mismatched base and surrounding nucleotides
  • DNA polymerase fills in the gap with the correct nucleotides

Double-Strand Break Repair Mechanisms

• Double-strand break repair mends broken DNA backbones caused by ionizing radiation, free radicals, or failed topoisomerase reactions
  • Homologous recombination repair uses the sister chromatid as a template to accurately repair the break
  • Non-homologous end joining directly ligates the broken ends together, which is more error-prone

Types of DNA Damage

UV-Induced Damage

• UV-induced damage results from exposure to ultraviolet radiation from the sun or artificial UV sources
  • UV light induces the formation of pyrimidine dimers (thymine dimers, cytosine dimers) that distort the DNA helix
  • Accumulation of pyrimidine dimers can lead to mutations and skin cancers (melanoma)
• Pyrimidine dimers are repaired by nucleotide excision repair or direct reversal by photolyase enzymes

Oxidative Damage

• Oxidative damage is caused by reactive oxygen species (ROS) generated during cellular metabolism or exposure to ionizing radiation
  • ROS oxidize DNA bases (8-oxoguanine, thymine glycol) and cause single-strand breaks
  • Accumulation of oxidative damage contributes to aging and degenerative diseases (Alzheimer's, Parkinson's)
• Oxidized bases are repaired primarily by base excision repair using DNA glycosylase enzymes

DNA Repair Enzymes

Excision Repair Enzymes

• DNA glycosylase initiates base excision repair by recognizing and removing damaged bases (oxidized, alkylated) to create an AP site
  • Uracil-DNA glycosylase removes uracil from DNA resulting from cytosine deamination
• Photolyase directly reverses UV-induced pyrimidine dimers by absorbing light energy and breaking the cyclobutane ring linking the pyrimidines
  • Found in bacteria and some eukaryotes but not placental mammals

Telomere Maintenance Enzyme

• Telomerase is a specialized reverse transcriptase that extends telomeres, the repetitive sequences at the ends of linear chromosomes
  • Telomerase uses its own RNA template to synthesize telomeric DNA repeats (TTAGGG in humans)
  • Maintains telomere length to prevent cellular senescence and chromosome instability
  • Highly active in stem cells and cancer cells but repressed in most somatic cells