DNA Repair Mechanisms: Structure, Types, and Pathways

DNA Repair Mechanisms

Introduction to DNA Damage and Repair

DNA is constantly exposed to damaging agents that can alter its structure and integrity. Cells have evolved multiple repair systems to detect and correct these changes, ensuring genetic stability and preventing mutations that could lead to disease.

• DNA damage results in structural changes that may impede replication or transcription.

• Repair systems recognize specific types of damage based on the nature and extent of structural distortion.

Types of DNA Damage

• Minor changes: Do not grossly distort DNA structure; often detected during transcription or replication when strands are separated.

• Major distortion: Sufficient to physically block replication or transcription.

• Strand breaks: Single-strand breaks (SSB) can be directly repaired by ligation; Double-strand breaks (DSB) are more severe and may lead to extensive DNA loss if not properly repaired.

Overview of DNA Repair Systems

Main DNA Repair Pathways

Cells utilize several distinct DNA repair mechanisms, each tailored to specific types of damage.

• I. Direct reversal: Repairs damage without DNA synthesis (e.g., photoreactivation).

• II. Excision repair: Damaged DNA is removed and resynthesized using the complementary strand as a template. Types include:

  • Base excision repair (BER)

  • Nucleotide excision repair (NER)

  • Mismatch excision repair (MMR)

• III. Recombination repair: Damaged DNA is removed and resynthesized using a homologous chromosome as a template (homologous recombination).

• IV. Non-homologous end joining (NHEJ): Directly joins broken DNA ends; error-prone.

• V. Translesion repair: DNA synthesis occurs without a template; highly error-prone.

Direct Reversal Repair

Photoreactivation

Some organisms, but not mammals, can repair UV-induced DNA damage through photoreactivation, a process mediated by the enzyme photolyase.

• Photolyase uses energy from visible light to break the bonds between thymine dimers caused by ultraviolet irradiation.

• This is known as "light repair"; other repair mechanisms are referred to as "dark repair".

Example: Escherichia coli can photoreactivate thymine dimers, but humans cannot.

Excision Repair Pathways

Base Excision Repair (BER)

BER corrects small, non-helix-distorting base lesions caused by oxidation, alkylation, or deamination.

• Damaged base is removed by a DNA glycosylase.

• Resulting abasic site is cleaved by an AP endonuclease.

• DNA polymerase fills the gap, and DNA ligase seals the strand.

Equation: $\text{DNA}_{\text{damaged base}} \xrightarrow{\text{glycosylase}} \text{DNA}_{\text{abasic site}} \xrightarrow{\text{AP endonuclease}} \text{DNA}_{\text{gap}} \xrightarrow{\text{Pol + Ligase}} \text{DNA}_{\text{repaired}}$

Nucleotide Excision Repair (NER)

NER removes bulky, helix-distorting lesions such as thymine dimers and chemical adducts.

• Damage is recognized by specific protein complexes (e.g., UvrAB in bacteria, XPC in mammals).

• Dual incisions are made on both sides of the lesion.

• Helicase removes the damaged oligonucleotide.

• DNA polymerase synthesizes new DNA, and ligase seals the strand.

Example: Defects in NER genes (XP genes) cause Xeroderma Pigmentosum in humans, leading to extreme sensitivity to sunlight and increased cancer risk.

Mismatch Excision Repair (MMR)

MMR corrects base mispairings that escape proofreading during DNA replication.

• Mismatch is recognized by MutS/MutL (bacteria) or MSH/MLH (eukaryotes).

• Newly synthesized strand is identified by nicks or methylation status.

• Excision of the error-containing segment is followed by resynthesis and ligation.

Equation: $\text{DNA}_{\text{mismatch}} \xrightarrow{\text{MMR complex}} \text{DNA}_{\text{gap}} \xrightarrow{\text{Pol + Ligase}} \text{DNA}_{\text{repaired}}$

Double-Strand Break Repair

Homologous Recombination Repair (HRR)

HRR uses a homologous sequence (usually the sister chromatid) as a template for accurate repair of double-strand breaks.

• Occurs primarily during S and G2 phases of the cell cycle.

• Highly faithful; preserves genetic information.

Non-Homologous End Joining (NHEJ)

NHEJ directly ligates broken DNA ends without a template, often resulting in small insertions or deletions.

• Predominant in G1 phase but available throughout the cell cycle.

• Error-prone; may lead to mutations.

Translesion DNA Synthesis

Translesion Repair

When replication is stalled by DNA lesions, specialized DNA polymerases can synthesize DNA across the damage without a template, allowing replication to continue but increasing the risk of mutations.

• Translesion polymerases are error-prone and lack proofreading activity.

• Used as a last resort to prevent cell death due to replication blockage.

Comparison of DNA Repair Pathways

Repair Pathway	Type of Damage	Template Used	Error Rate
Direct Reversal	Simple chemical modifications (e.g., thymine dimers)	None	Low
Base Excision Repair	Small, non-distorting base lesions	Complementary strand	Low
Nucleotide Excision Repair	Bulky, helix-distorting lesions	Complementary strand	Low
Mismatch Repair	Replication errors (mismatches)	Complementary strand	Low
Homologous Recombination	Double-strand breaks	Homologous chromosome/sister chromatid	Very low
Non-Homologous End Joining	Double-strand breaks	None	High
Translesion Synthesis	Replication-blocking lesions	None	Very high

Summary

• DNA repair is essential for maintaining genetic stability and preventing disease.

• Multiple repair pathways exist, each specialized for different types of damage.

• Defects in repair systems can lead to increased mutation rates and disease susceptibility.

Additional info: Some details on the molecular mechanisms and protein complexes involved in repair pathways were inferred and expanded for academic completeness.