Biology for AP Courses · DNA Structure and Function
DNA Repair
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In 30 seconds
DNA is remarkably stable, but not inert. Every day the DNA in a human cell is damaged thousands of times by ultraviolet light, ionizing radiation, reactive oxygen species, and the chemistry of water itself (bases fall off or get altered). Replication adds its own errors — roughly one mistake per 10⁵–10⁶ nucleotides even after proofreading (commonly taught estimates). If every lesion Any chemical change to DNA deviating from normal structure Full entry → became a permanent mutation, cells would accumulate errors faster than life could tolerate.
Cells therefore run several overlapping repair systems, each specialized for a class of damage: direct reversal for a few specific lesions, base excision repair (BER) for small chemical alterations, nucleotide excision repair (NER) Excises a ~24–32 nt patch around bulky lesions Full entry → for bulky, helix-distorting damage like thymine dimers, mismatch repair (MMR) Corrects mis-pairs that escaped proofreading Full entry → for errors past proofreading, and double-strand break repair — non-homologous end joining (NHEJ) Direct re-joining of broken DNA ends, often with small deletions Full entry → and homologous recombination (HR) Repair of a break using the sister chromatid as a template Full entry → — for broken chromosomes. When these fail, mutations accumulate, driving cancer and aging.
Why this matters
DNA repair sits at the intersection of genetics, cancer biology, and medicine. Inherited repair defects cause dramatic disease: people with xeroderma pigmentosum cannot repair thymine dimers and develop skin cancers very young; people with Lynch syndrome carry defective mismatch-repair genes and face greatly elevated colorectal cancer risk; people with certain BRCA1 or BRCA2 mutations have impaired homologous recombination and elevated breast and ovarian cancer risk. Cancer treatments exploit repair too: radiation and many chemotherapy drugs damage DNA, overwhelming repair in dividing cancer cells. Understanding repair explains why sun exposure causes skin cancer (UV → thymine dimers) and why repair pathways are drug targets. On the AP exam, the classic questions: which repair system handles which damage, and what happens when it fails.
The college version
Core Concepts
Where the damage comes from
- Replication errors: mis-pairs escape proofreading (3′→5′ exonuclease).
- Depurination: a purine (A or G) falls off its sugar, leaving an AP site ("without a base") — among the most frequent spontaneous lesions.
- Deamination: cytosine becomes uracil — not normally in DNA, so the cell recognizes it as damage.
- UV light: adjacent pyrimidines (often two thymines) fuse into a thymine dimer Two adjacent thymines fused by UV light Full entry →, kinking the helix.
- Ionizing radiation and free radicals: can oxidize bases (e.g., 8-oxoguanine) or snap the backbone (double-strand breaks).
- Chemicals: alkylating agents and bulky mutagens attach groups to bases.
Direct reversal: fixing the lesion in place
A few lesions are repaired by reversing the chemistry — no cutting required. Photolyase, found in bacteria, fungi, plants, and some animals, splits thymine dimers using visible light (photoreactivation); humans lack it, which is why sunlight is more dangerous for us. O⁶-methylguanine methyltransferase (MGMT) removes alkyl groups from guanine by taking them onto itself (the enzyme is consumed). Fast and error-free, but covers only a narrow set of lesions.
Base excision repair (BER): the small-lesion specialist
BER handles small, non-helix-distorting damage such as deaminated or oxidized bases. A DNA glycosylase Enzyme that removes a damaged base from its sugar Full entry → snips out the damaged base, creating an AP site; an AP endonuclease cuts the backbone; a polymerase replaces one (or a few) nucleotides; DNA ligase seals the nick — like replacing a single defective letter in a sentence.
Nucleotide excision repair (NER): the bulky-lesion specialist
NER handles bulky, helix-distorting lesions — above all thymine dimers and large chemical adducts. The machinery detects the distortion, unwinds the DNA, excises an oligonucleotide of roughly 24–32 nucleotides (commonly taught figures vary), fills the gap with a polymerase, and seals with ligase. Two flavors exist: global genome NER scans the whole genome; transcription-coupled NER triggers when RNA polymerase stalls at a lesion in an active gene. In humans, defects in NER genes (XPA–XPG) cause xeroderma pigmentosum: people with it develop skin cancers in childhood because thymine dimers are never removed.
Mismatch repair (MMR): the proofreader's backup
MMR corrects errors that escape proofreading — mis-paired bases that are chemically normal but simply wrong. The challenge is knowing which strand is the mistake: MMR must fix the new strand, not the template. In bacteria, hemimethylation State where only the parental strand is methylated Full entry → answers it: the parental strand is methylated, the new strand is not, so the machinery (MutS, MutL, MutH) cuts the unmethylated strand. Eukaryotes use homologs (MSH, MLH) with similar logic; defects cause Lynch syndrome, with high lifetime risk of colorectal and other cancers.
Double-strand break repair: two strategies
A broken chromosome is the most lethal damage — one unrepaired double-strand break can kill a cell. Two strategies with opposite trade-offs:
- Non-homologous end joining (NHEJ): Ku proteins bind the broken ends and ligase IV stitches them together — fast, any cell-cycle phase, but error-prone, possibly deleting or adding nucleotides; handles most breaks in G1.
- Homologous recombination (HR): the cell uses the sister chromatid (available in S and G2) as a template to rebuild the region precisely with Rad51 — slow, needs a homolog, but error-free. BRCA1 and BRCA2 participate, which is why their loss predisposes to cancer.
Common Confusions
| Do Not Confuse | With | The Difference |
|---|---|---|
| BER | NER | BER fixes small, non-distorting lesions (deaminated/oxidized bases), replacing 1–few nucleotides; NER fixes bulky, helix-distorting lesions (thymine dimers), replacing ~24–32 nt |
| DNA damage | Mutation | Damage is a chemical change to DNA; mutation is a heritable sequence change. Repair happens before damage becomes mutation |
| Proofreading | Mismatch repair | Proofreading is the polymerase's 3′→5′ exonuclease during synthesis; MMR acts after to catch what slipped through |
| NHEJ | Homologous recombination | NHEJ: fast, error-prone, any time, no template; HR: slow, error-free, needs a sister chromatid (S/G2) |
| Photolyase | NER | Photolyase splits thymine dimers with light — humans don't have it and rely on NER |
| Xeroderma pigmentosum | Lynch syndrome | XP = NER defect → skin cancers from UV; Lynch = MMR defect → colorectal cancers from replication errors |
Eli explains
The same idea, in plain words
Explain it like I’m 10
Think of your DNA as a recipe book your body copies over and over. Sometimes a letter gets smudged, a page gets a coffee stain, or a page tears in half. The cell has different repair crews: one erases small smudges, one cuts out big stains and rewrites the page, one checks new copies for typos, and one tapes torn pages back together — quickly with messy tape (NHEJ) or carefully from a backup book (HR). If the crews are missing, the recipes come out wrong, and that's how cancer starts.
Worked example
Picture a person with xeroderma pigmentosum spending an afternoon in strong sunlight. UV photons strike DNA in their skin cells and fuse adjacent thymines into dimers. In most people, the NER machinery detects each kink, unwinds the helix, and excises the ~24–32 nucleotide patch containing the dimer; a polymerase refills the gap and ligase seals it — no mutation. In this person's cells, an NER protein (one of the XPA–XPG factors) is missing, so the dimers stay put. When the DNA is later replicated, the polymerase stalls at the dimer and bypasses it incorrectly, introducing sequence errors; over years, mutations in skin cells push them toward cancer. Now the contrast: a person with Lynch syndrome has intact NER but defective mismatch repair, so UV dimers are handled fine — their elevated risk comes instead from replication errors in rapidly dividing tissues like the colon lining, where mis-pairs that escape proofreading are never corrected. Two repair failures, two diseases, one lesson: each repair pathway is a specialist, and losing any one raises the odds of mutation-driven disease.
Key takeaways
- Proofreading ≠ repair: the polymerase's 3′→5′ exonuclease catches errors during synthesis; MMR catches the rest after.
- BER fixes small lesions (deamination, oxidation, depurination): glycosylase → AP site → AP endonuclease → polymerase + ligase.
- NER fixes bulky, helix-distorting lesions (thymine dimers): excises a ~24–32 nt patch. Defects → xeroderma pigmentosum.
- Humans lack photolyase — no direct thymine-dimer repair; we rely on NER.
- MMR fixes mis-pairs that escaped proofreading; bacteria distinguish strands by hemimethylation. Defects → Lynch syndrome.
- NHEJ = fast, error-prone, any phase; HR = slow, error-free, needs sister chromatid (S/G2). BRCA1/2 work in HR.
- One unrepaired double-strand break can kill a cell; one unrepaired thymine dimer can mutate a gene.
Check yourself
6 review questions from the chapter. Try each one, then open the answer.
List four types of DNA damage and the repair system that handles each.
Show answer
Replication mis-pairs → mismatch repair (MMR); deaminated/oxidized bases and AP sites → base excision repair (BER); thymine dimers and bulky adducts → nucleotide excision repair (NER); double-strand breaks → NHEJ or homologous recombination; alkylated guanine → direct reversal.
Why can't humans just "photoreactivate" away thymine dimers?
Show answer
Humans lack photolyase — no light-powered enzyme to split thymine dimers — so we excise and resynthesize the patch via NER.
What is the key difference between how BER and NER deal with damage?
Show answer
BER removes just the damaged base (glycosylase) and replaces one to a few nucleotides; NER recognizes a distorted helix, cuts out a long oligonucleotide (~24–32 nt), and resynthesizes it.
How does a bacterial cell know which strand of a mismatched base pair is the new, erroneous strand?
Show answer
By methylation (hemimethylation): the parental strand is methylated, the new strand is not, so MMR cuts and repairs the unmethylated strand.
Why is homologous recombination considered error-free while NHEJ is not?
Show answer
HR uses the sister chromatid as a template, rebuilding the original sequence exactly; NHEJ just joins the broken ends, possibly deleting or adding bases at the junction.
Explain how a defect in one repair pathway (e.g., NER) can lead to cancer.
Show answer
Unrepaired damage (e.g., a thymine dimer) stalls or misleads the replication machinery, producing a permanent sequence change (mutation). If the mutation hits a gene controlling cell division — an oncogene or tumor suppressor — the cell may divide out of control, and more mutations accumulate into cancer.
Study tools & related lessonsKey vocabulary · Related
Key vocabulary
- lesion
- Any chemical change to DNA deviating from normal structure
- thymine dimer
- Two adjacent thymines fused by UV light
- DNA glycosylase
- Enzyme that removes a damaged base from its sugar
- nucleotide excision repair (NER)
- Excises a ~24–32 nt patch around bulky lesions
- mismatch repair (MMR)
- Corrects mis-pairs that escaped proofreading
- hemimethylation
- State where only the parental strand is methylated
- non-homologous end joining (NHEJ)
- Direct re-joining of broken DNA ends, often with small deletions
- homologous recombination (HR)
- Repair of a break using the sister chromatid as a template
Sources & references
This lesson was adapted from the open educational references above; their licenses and attributions are preserved. See Copyright & Licensing.
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