DNA Repair Pathways

DNA Repair Pathways

Cells possess multiple DNA repair pathways to maintain genomic integrity. Each pathway is specialized for different types of DNA damage, and the choice of pathway depends on the nature of the lesion and cell cycle stage.

Single-Strand Repair

• Base Excision Repair (BER): Repairs small lesions from oxidation, alkylation, or deamination. Glycosylases remove damaged bases, AP endonuclease cleaves the backbone, and polymerase/ligase fill the gap.
• Nucleotide Excision Repair (NER): Repairs bulky adducts like UV-induced pyrimidine dimers. Excises a ~30nt segment containing the damage and fills the gap.
• Mismatch Repair (MMR): Corrects base-base mismatches and insertion/deletion loops from replication errors. MutS/MutL homologs recognize mismatches and direct excision.

Double-Strand Break Repair

• Homologous Recombination (HR): Uses sister chromatid as template for error-free repair. Active primarily in S/G2 phases. Involves BRCA1/2, RAD51, and extensive end resection.
• Non-Homologous End Joining (NHEJ): Directly ligates broken ends without template. Active throughout cell cycle but error-prone. Uses Ku70/80, DNA-PKcs, and ligase IV.

Pathway Choice

The choice between HR and NHEJ for DSB repair is influenced by cell cycle stage and DNA end processing. BRCA1 promotes HR by facilitating end resection, while 53BP1 promotes NHEJ by blocking resection.

Consequences of Repair Failure

Unrepaired or misrepaired damage leads to mutations, chromosomal aberrations, or cell death. Defects in repair pathways cause cancer predisposition syndromes (e.g., Lynch syndrome from MMR defects, hereditary breast/ovarian cancer from BRCA mutations).