5.2 DNA repair pathways and mechanisms

DNA repair pathways are your body's superheroes, swooping in to fix radiation-induced damage. From base excision repair zapping oxidized bases to nucleotide excision repair tackling bulky lesions, these mechanisms work tirelessly to maintain genetic integrity.

Double-strand break repair is the heavy hitter, using homologous recombination or non-homologous end joining to mend the most severe DNA wounds. Meanwhile, specialized repair mechanisms like mismatch repair and direct reversal add extra layers of protection against radiation's harmful effects.

DNA Repair Pathways

Base Excision and Nucleotide Excision Repair

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• Base excision repair (BER) addresses oxidative damage to DNA bases caused by ionizing radiation
  • Removes individual damaged bases
  • Utilizes DNA glycosylases to recognize and excise damaged bases
  • Creates apurinic/apyrimidinic (AP) sites for further processing
• Nucleotide excision repair (NER) removes bulky DNA lesions
  • Excises larger segments of nucleotides containing damage
  • Repairs UV radiation-induced damage and certain ionizing radiation-induced lesions
  • Involves recognition, incision, excision, synthesis, and ligation steps

Double-Strand and Single-Strand Break Repair

• Double-strand break repair (DSBR) fixes radiation-induced double-strand breaks through two main pathways
  • Homologous recombination (HR) uses a homologous template for accurate repair
  • Non-homologous end joining (NHEJ) directly ligates broken ends without a template
• Single-strand break repair (SSBR) addresses common radiation-induced single-strand breaks
  • Often utilizes components of the BER pathway
  • Involves detection, end processing, gap filling, and ligation steps

Specialized Repair Mechanisms

• Mismatch repair (MMR) corrects base mismatches and small insertions/deletions
  • Targets errors that occur during DNA replication
  • Becomes particularly important under radiation-induced replication stress
• Direct reversal repair reverses specific types of DNA damage without excision
  • Directly corrects chemical modifications (O6-methylguanine)
  • Operates through specialized enzymes (O6-methylguanine DNA methyltransferase)

DNA Repair Mechanisms: Comparisons

Excision Repair Pathways

• BER and NER both involve damaged DNA excision but differ in scale
  • BER removes individual bases (thymine glycol)
  • NER excises larger nucleotide segments (6-4 photoproducts)
• BER typically repairs smaller lesions while NER handles bulkier damages
  • BER addresses oxidative damage (8-oxoguanine)
  • NER removes UV-induced dimers (cyclobutane pyrimidine dimers)

Double-Strand Break Repair Strategies

• HR and NHEJ both repair double-strand breaks but differ in accuracy and template requirement
  • HR requires a homologous template, typically a sister chromatid
  • NHEJ directly ligates broken ends without a template
• HR operates mainly in S and G2 phases, while NHEJ functions throughout the cell cycle
  • HR provides more accurate repair (preserves original sequence)
  • NHEJ is faster but more error-prone (potential for insertions/deletions)

Specialized vs. General Repair Mechanisms

• MMR specifically targets replication errors, unlike BER and NER
  • Corrects base mismatches (G-T mismatches)
  • Repairs small insertions/deletions (1-4 nucleotide loops)
• Direct reversal repair uniquely reverses damage without DNA excision
  • Removes alkyl groups from guanine (O6-methylguanine)
  • Contrasts with excision-based methods of BER and NER

Key Players in DNA Repair

Enzymes in Base Excision Repair

• DNA glycosylases recognize and remove damaged bases in BER
  • Different glycosylases target specific types of damage (uracil-DNA glycosylase)
  • Create AP sites for further processing
• AP endonucleases cleave the DNA backbone at AP sites
  • Prepare DNA for subsequent repair steps (APE1)
  • Generate 3'-OH termini for DNA synthesis

Polymerases and Ligases

• DNA polymerases synthesize new DNA to replace excised damaged sections
  • Pol β in BER fills short gaps
  • Pol δ and ε in NER perform longer stretch synthesis
• DNA ligases seal nicks in the DNA backbone after repair synthesis
  • Ligase III in BER and SSBR
  • Ligase I in NER and long-patch BER

Double-Strand Break Repair Proteins

• MRN complex (Mre11-Rad50-Nbs1) detects and processes double-strand breaks
  • Initiates both HR and NHEJ pathways
  • Performs end resection for HR
• Rad51 facilitates homology search and strand invasion in HR
  • Forms nucleoprotein filaments on ssDNA
  • Catalyzes homologous pairing and strand exchange
• Ku70/80 and DNA-PKcs are key components of NHEJ
  • Bind to DNA ends and facilitate their alignment
  • Recruit additional factors for end processing and ligation

Efficiency vs Limitations of DNA Repair

Pathway-Specific Efficiencies

• BER efficiently repairs single base modifications
  • Rapid response to common oxidative damages (8-oxoguanine)
  • May be overwhelmed by extensive damage from high radiation doses
• NER handles a wide variety of bulky DNA lesions
  • Effectively removes UV-induced damages (cyclobutane pyrimidine dimers)
  • Slower process compared to BER
  • Less effective in non-transcribed genomic regions

Cell Cycle Dependence and Accuracy

• HR provides high-fidelity repair of double-strand breaks
  • Limited to S and G2 phases when sister chromatids are available
  • Ensures accurate repair in actively dividing cells
• NHEJ operates throughout the cell cycle but with lower accuracy
  • More error-prone than HR (potential for small deletions or insertions)
  • Faster response to DSBs in non-dividing cells

Limitations and Challenges

• High doses of radiation can compromise repair pathway efficiency
  • Extensive damage may saturate repair mechanisms
  • Cellular energy depletion can impair repair processes
• Complex DNA lesions may evade normal repair processes
  • Clustered damages from high-LET radiation challenge repair machinery
  • Some lesions persist, leading to genomic instability or cell death
• MMR efficiency may decrease in cells with high mutation rates
  • Chronic low-dose radiation exposure can overwhelm MMR capacity
  • Leads to increased genomic instability over time