DNA Damage and Repair Pathways

The lesions that constantly threaten the genome and the dedicated enzymatic pathways that recognise, excise, and resynthesise damaged DNA to keep the sequence intact.

Definition

DNA repair pathways are the enzymatic systems that detect specific classes of DNA lesion or mispairing and restore the original sequence, typically by removing the damaged region and resynthesising it using the complementary strand or a homologous template.

Scope

This topic surveys the principal types of DNA damage — base modifications, abasic sites, bulky adducts, mismatches, and strand breaks — and the repair pathways matched to each: direct reversal, base excision repair, nucleotide excision repair, mismatch repair, and double-strand break repair by homologous recombination and non-homologous end joining. It treats the logic and steps of each pathway, not the clinical management of repair-deficiency disorders.

Core questions

• What are the major kinds of DNA damage and where do they come from?
• How does a cell match each type of lesion to the right repair pathway?
• How are single damaged bases removed and replaced without losing information?
• How are double-strand breaks, the most dangerous lesions, repaired?

Key theories

Lesion-matched repair pathways

Cells maintain several specialised pathways, each tuned to a class of damage — base excision repair for small base lesions, nucleotide excision repair for bulky helix-distorting adducts, and mismatch repair for replication errors — so that the appropriate machinery is recruited to each lesion.

Template-directed restoration

Because DNA is double-stranded, most repair removes the damaged stretch from one strand and uses the intact complementary strand (or, for breaks, a homologous duplex) as a template to restore the correct sequence.

Mechanisms

In base excision repair, a DNA glycosylase removes a damaged base, an endonuclease cleaves a gap, and polymerase and ligase fill and seal it. Nucleotide excision repair recognises bulky distortions, excises a short oligonucleotide containing the lesion, and resynthesises the gap. Mismatch repair detects post-replicative mispairs, identifies and removes the newly made strand, and resynthesises it. Double-strand breaks are repaired either by homologous recombination, which copies the missing information from a sister duplex, or by non-homologous end joining, which directly ligates the broken ends.

Clinical relevance

Inherited defects in these pathways cause disorders marked by sensitivity to mutagens and elevated cancer risk, and many cancer therapies exploit tumour repair deficiencies; this entry frames such links as significance and provides no diagnostic or treatment guidance.

History

Through the late twentieth century, biochemists dissected the distinct repair pathways now standard in textbooks — base excision, nucleotide excision, and mismatch repair — work recognised by the 2015 Nobel Prize in Chemistry to Lindahl, Sancar, and Modrich for mechanistic studies of DNA repair.

Key figures

• Tomas Lindahl
• Aziz Sancar
• Paul Modrich

Seminal works

• alberts2014
• watson2013

Frequently asked questions

Why are double-strand breaks especially dangerous?

Both strands are severed at once, so there is no intact complementary strand nearby to template repair; misrepair can cause large deletions or chromosome rearrangements.

How does mismatch repair know which base is wrong?

It targets the newly synthesised strand, which carries transient signals distinguishing it from the template, so the original correct base is preserved.