Part 4: DNA Repair Mechanisms
Maintaining Genome Integrity
DNA is constantly damaged by environmental factors and metabolic byproducts. Cells have evolved sophisticated repair mechanisms to maintain genomic integrity. Defects in DNA repair are associated with cancer, aging, and genetic disorders.
Types of DNA Damage
Oxidative Damage
Cause: ROS, metabolic byproducts
Example: 8-oxoguanine
Alkylation
Cause: Alkylating agents
Example: O6-methylguanine
UV Damage
Cause: Ultraviolet radiation
Example: Thymine dimers
Deamination
Cause: Spontaneous hydrolysis
Example: C โ U conversion
Double-strand breaks
Cause: Ionizing radiation, replication errors
Example: Chromosome breaks
Mismatches
Cause: Replication errors
Example: G-T mispairing
Repair Pathways
Base Excision Repair (BER)
Repairs small, non-helix-distorting lesions
Nucleotide Excision Repair (NER)
Repairs bulky, helix-distorting lesions (UV damage)
Mismatch Repair (MMR)
Corrects replication errors and small insertions/deletions
Double-Strand Break Repair
NHEJ
Non-homologous end joining. Fast but error-prone.
HR
Homologous recombination. Accurate but requires template.
Clinical Significance
Xeroderma Pigmentosum
Defective NER โ UV sensitivity, skin cancer
BRCA1/2 Mutations
Defective HR โ breast/ovarian cancer
Lynch Syndrome
Defective MMR โ colorectal cancer
Ataxia Telangiectasia
Defective ATM โ radiation sensitivity