DNA repair questions test one skill: match the lesion to the pathway, then the pathway to the disease. UV-induced pyrimidine (thymine) dimers and other bulky, helix-distorting lesions → nucleotide excision repair (NER; xeroderma pigmentosum); a single damaged base (deaminated, oxidized or alkylated) → base excision repair (BER; MUTYH-associated polyposis); replication mismatches and small insertion-deletion loops → mismatch repair (MMR; Lynch syndrome with microsatellite instability); double-strand breaks → homologous recombination (HR; accurate, uses the sister chromatid, BRCA1/2) or nonhomologous end joining (NHEJ; no template, error-prone). Add the Fanconi anemia pathway for interstrand crosslinks and ATM, the double-strand break sensor lost in ataxia-telangiectasia, and you have the whole topic.
The one-page map: lesion → pathway
| Damage | Usual cause | Pathway | How the repair works |
|---|---|---|---|
| Pyrimidine (thymine) dimers; bulky adducts that distort the helix | UV light; bulky chemicals | NER | Endonucleases cut out a stretch of about 30 nucleotides around the lesion; DNA polymerase fills the gap and ligase seals it |
| One abnormal base: uracil from cytosine deamination, oxidized guanine, alkylated bases | Spontaneous chemistry, reactive oxygen species, alkylating agents | BER | A DNA glycosylase removes the base, leaving an AP (abasic) site; AP endonuclease nicks the backbone; polymerase and ligase finish |
| Mismatched base or small insertion-deletion loop in new DNA | Replication errors that escaped proofreading | MMR | MutS homologs (MSH2, MSH6) recognize the error; MutL homologs (MLH1, PMS2) direct removal of the faulty stretch of the new strand, which is then resynthesized |
| Double-strand break, after replication | Ionizing radiation, some chemotherapy, broken replication forks | HR | The sister chromatid is the template, so repair is accurate; promoted in S and G2 |
| Double-strand break, any phase | Same | NHEJ | Broken ends are joined directly without a template; fast, but nucleotides can be lost or added |
| Interstrand crosslink | Crosslinking chemotherapy such as cisplatin | Fanconi anemia pathway | Switched on when the crosslink blocks replication; the crosslink is removed and HR proteins such as BRCA2 (FANCD1) finish the repair |
| Lesion that stalls the replication fork | Unrepaired UV damage | Translesion synthesis | Specialized polymerases such as polymerase η copy past the lesion: damage tolerance, not true repair |
| O6-methylguanine | Alkylating agents | Direct reversal | O6-methylguanine methyltransferase (MGMT) moves the methyl group onto its own cysteine |
Memory hooks
- BER = one Base; NER = a Nucleotide patch; MMR = Mistakes of replication; HR = Homolog as template, High fidelity; NHEJ = No homology, Not perfect.
- BER order, "GEL PLease": Glycosylase → Endonuclease → Lyase → Polymerase → Ligase.
- Size rule: if the damage bends the helix (dimers, bulky adducts), cut out a patch (NER); if it is one bad base, pluck the base (BER).
- Timing rule: HR needs a sister chromatid, so it works after replication (S and G2); NHEJ works throughout the cell cycle and is the main option before replication (G1).
Diseases of DNA repair: the cheat table
| Syndrome | Gene and pathway | Inheritance | Classic clues | Cancers |
|---|---|---|---|---|
| Xeroderma pigmentosum | XPA–XPG (NER); variant type POLH (translesion polymerase η) | AR | About half get severe sunburn after minutes of sun; almost all have freckling in sun-exposed skin by age 2; photophobia; about 30% develop progressive neurologic problems | First skin cancer usually before age 10; about 10,000× the risk of nonmelanoma skin cancer and up to 2,000× the melanoma risk |
| Cockayne syndrome | ERCC6, ERCC8 (transcription-coupled NER) | AR | Photosensitivity with microcephaly, short stature, hearing and vision loss; severe liver reaction to metronidazole | No predisposition to skin cancer; growth failure, developmental delay and neurologic decline dominate |
| Lynch syndrome (HNPCC) | MLH1, MSH2, MSH6, PMS2, or EPCAM (which silences MSH2) (MMR) | AD | About 1 in 279 people in the US carry a variant; polyps appear younger but are not more numerous; tumors show microsatellite instability | Colorectal and endometrial, plus ovarian, stomach, small bowel, liver and bile duct, urinary tract, brain and skin; usually in the 40s or 50s |
| MUTYH-associated polyposis | MUTYH (BER glycosylase that removes adenine mispaired with oxidized guanine) | AR | 10 to hundreds of colon polyps, usually by about age 50 | Colorectal cancer risk of 80–90% without surveillance |
| Hereditary breast and ovarian cancer | BRCA1, BRCA2 (HR) | AD | Family history of early breast, ovarian, prostate or pancreatic cancer | Breast above 60% (vs about 13%); ovarian 39–58% (BRCA1) and 13–29% (BRCA2) (vs about 1.1%) |
| Fanconi anemia | More than 20 genes; 80–90% of cases FANCA, FANCC or FANCG; biallelic BRCA2 (FANCD1) or BRCA1 (FANCS) cause subtypes (crosslink repair) | Mostly AR; rarely AD or X-linked | Bone marrow failure in about 90%; short stature; malformed thumbs or forearms; café-au-lait spots; diagnosed by chromosome breakage analysis | AML and tumors of the head and neck, GI tract, liver and genital tract (10–30%) |
| Ataxia-telangiectasia | ATM (kinase that recognizes double-strand breaks and coordinates their repair and cell division) | AR | Ataxia before age 5; telangiectasias of eyes and skin; weak immunity with lung infections; high alpha-fetoprotein; very sensitive to radiation, including x-rays | Leukemia and lymphoma |
| Bloom syndrome | BLM (RecQ helicase that limits sister chromatid exchange) | AR | Short stature, sun-sensitive butterfly rash, recurrent respiratory infections; overrepresented in Ashkenazi Jewish families | Greatly increased cancer risk |
Deeper dives: the Lynch syndrome comparison table, FAP vs MUTYH-associated polyposis and the aplastic anemia flowchart, where Fanconi anemia is the inherited cause to remember.
Double-strand breaks: HR vs NHEJ
| Feature | Homologous recombination | Nonhomologous end joining |
|---|---|---|
| Template | Homologous sequence, usually the sister chromatid | None |
| Cell cycle | Promoted in S and G2 | Throughout the cell cycle; the main option in G1 |
| Accuracy | High fidelity | Error-prone: small deletions or insertions at the join |
| Key players | BRCA1 promotes HR; BRCA2 recruits RAD51, which coats the broken strand and invades the template | End-binding and ligation proteins; no homology search |
| Disease link | BRCA1/2 cancers, Fanconi anemia, Bloom syndrome | Review tables often file ataxia-telangiectasia here, but ATM senses breaks upstream of both pathways |
| Other jobs | Crossing over in meiosis | Joining gene segments during V(D)J recombination in developing lymphocytes |
PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib) are FDA-approved for certain cancers with harmful BRCA1 or BRCA2 variants. The logic is synthetic lethality: PARP works in base excision repair of single-strand breaks, and blocking it leaves lesions that are normally fixed by HR. Tumor cells that have lost both BRCA copies cannot repair them and die, while the patient's normal cells keep one working copy and functional HR. Biallelic BRCA1 or BRCA2 variants cause Fanconi anemia subtypes, with solid tumors and AML, often in childhood.
Exam traps
- NER vs BER is about size. Bulky, helix-distorting damage → NER removes a patch; one small base lesion → BER removes one base.
- MMR is not proofreading. Proofreading is the polymerase's own 3′→5′ exonuclease during synthesis; MMR fixes what escapes it, on the newly made strand. Microsatellites are where slipped strands and small loops pile up when MMR fails, which is why Lynch tumors show microsatellite instability and frameshifts (see point vs frameshift mutations).
- "Nonpolyposis" still means polyps. Lynch polyps arrive earlier, not in greater numbers. Many adenomas point instead to FAP (APC, dominant) or MUTYH-associated polyposis (recessive, BER; 10 to hundreds).
- XP vs Cockayne: both are photosensitive NER disorders, but XP means early skin cancers, while Cockayne means growth failure, microcephaly and neurologic problems.
- XP variant: POLH variants knock out polymerase η, the translesion polymerase that copies past UV damage; this type typically lacks the neurologic problems.
- Ataxia-telangiectasia is a sensing defect. ATM detects double-strand breaks and coordinates repair and cell-cycle control, so x-rays and radiotherapy are dangerous. If a question forces a pathway, choose double-strand break repair.
- Fanconi anemia = crosslinks. Cells break chromosomes when exposed to crosslinking agents, the basis of the diagnostic chromosome breakage test.
- Inheritance: Lynch and BRCA1/2 are dominant cancer syndromes; XP, Cockayne, MUTYH polyposis, Fanconi anemia (mostly), A-T and Bloom are recessive.
Practice question
Vignette. A 6-year-old boy has had blistering sunburns after a few minutes outdoors since infancy, and dense freckling developed on his face, neck and forearms before age 2. Bright light hurts his eyes. A rough, bleeding lesion on his nose is biopsied and shows squamous cell carcinoma. His parents are first cousins and are unaffected. A defect in which DNA repair process best explains his condition?
- A. Base excision repair
- B. Homologous recombination
- C. Mismatch repair
- D. Nonhomologous end joining
- E. Nucleotide excision repair
Answer: E. UV light creates pyrimidine (thymine) dimers that distort the helix, and NER cuts them out. Xeroderma pigmentosum is autosomal recessive (consanguineous, unaffected parents) and causes freckling by age 2, photophobia and skin cancer that usually starts before age 10.
Why the others are wrong:
- A. Base excision repair: fixes single damaged bases; its classic disease, MUTYH-associated polyposis, causes colon adenomas and colorectal cancer in adults, not childhood skin cancer.
- B. Homologous recombination: accurate double-strand break repair; heterozygous BRCA1/2 variants cause adult breast, ovarian, prostate and pancreatic cancers in a dominant pattern.
- C. Mismatch repair: Lynch syndrome is dominant and causes MSI-high colorectal and endometrial cancers, usually in the 40s or 50s.
- D. Nonhomologous end joining: repairs double-strand breaks from ionizing radiation; the classic radiosensitive picture is ataxia-telangiectasia (ataxia, telangiectasias, infections), not sunlight sensitivity.
Key takeaways
- NER: bulky lesions and UV thymine dimers; defective in xeroderma pigmentosum (and, for transcription-coupled NER, Cockayne syndrome).
- BER: one damaged base, glycosylase first ("GEL PLease"); MUTYH polyposis is recessive.
- MMR: replication mismatches and loops; Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM), microsatellite instability.
- HR: accurate double-strand break repair from the sister chromatid in S/G2; BRCA1/2; PARP inhibitors exploit HR loss.
- NHEJ: template-free, error-prone, works throughout the cell cycle.
- Specials: crosslinks → Fanconi anemia; break sensing → ATM (ataxia-telangiectasia); RecQ helicase → Bloom syndrome; polymerase η → XP variant.
Sources
- DNA Repair, in The Cell: A Molecular Approach, 2nd edition — NCBI Bookshelf
- Jasin M, Rothstein R. Repair of Strand Breaks by Homologous Recombination — Cold Spring Harbor Perspectives in Biology (2013)
- Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy — Nature (2005)
- Xeroderma pigmentosum — MedlinePlus Genetics
- Cockayne Syndrome — GeneReviews, NCBI Bookshelf (last update 2024)
- Lynch syndrome — MedlinePlus Genetics
- MUTYH-associated polyposis — MedlinePlus Genetics
- BRCA Gene Changes: Cancer Risk and Genetic Testing — National Cancer Institute
- Fanconi anemia — MedlinePlus Genetics
- Fanconi Anemia — GeneReviews, NCBI Bookshelf (last update 2026)
- Ataxia-telangiectasia — MedlinePlus Genetics
- Bloom syndrome — MedlinePlus Genetics
Frequently Asked Questions
What are the main DNA repair mechanisms?
The five pathways tested most are nucleotide excision repair for bulky, helix-distorting lesions such as UV-induced thymine dimers; base excision repair for a single damaged base; mismatch repair for replication errors in newly made DNA; and two pathways for double-strand breaks, homologous recombination and nonhomologous end joining. The Fanconi anemia pathway handles interstrand crosslinks, and translesion polymerases let replication continue past unrepaired damage.
What is the difference between nucleotide excision repair and base excision repair?
Nucleotide excision repair removes bulky damage that distorts the double helix, such as UV-induced pyrimidine dimers, by cutting out a stretch of about 30 nucleotides and resynthesizing it. Base excision repair handles a single small base lesion, such as uracil from cytosine deamination or oxidized guanine: a glycosylase removes the base, and an AP endonuclease, polymerase and ligase finish the job. Xeroderma pigmentosum is an NER defect, and MUTYH-associated polyposis is a BER defect.
Which DNA repair defect causes xeroderma pigmentosum?
Xeroderma pigmentosum is caused by defective nucleotide excision repair, so UV-induced pyrimidine dimers are not removed; a variant form is caused by loss of DNA polymerase eta, which copies past UV damage. It is autosomal recessive and causes extreme sun sensitivity, freckling by age 2 and skin cancers that usually begin before age 10. About 30 percent of affected people also develop progressive neurologic problems.
What is the difference between homologous recombination and nonhomologous end joining?
Both repair double-strand breaks. Homologous recombination copies the missing sequence from the sister chromatid, so it is accurate but works mainly in the S and G2 phases, and it depends on BRCA1 and BRCA2. Nonhomologous end joining ligates the broken ends directly without a template, works throughout the cell cycle, and can lose or add a few nucleotides at the join.
Which DNA repair pathway is defective in Lynch syndrome?
Lynch syndrome is caused by a germline variant in a mismatch repair gene, MLH1, MSH2, MSH6 or PMS2, or by an EPCAM deletion that silences MSH2. It is autosomal dominant, and tumors show microsatellite instability because replication errors in repetitive sequences go unrepaired. Colorectal and endometrial cancers are the most common, usually in the 40s or 50s.
Which DNA repair problems cause Fanconi anemia and ataxia-telangiectasia?
Fanconi anemia is a defect in the pathway that repairs interstrand crosslinks, which relies on homologous recombination proteins such as BRCA2 to finish the repair; it causes bone marrow failure, thumb and forearm anomalies and a high risk of AML, and chromosome breakage testing confirms it. Ataxia-telangiectasia is caused by loss of ATM, the kinase that recognizes double-strand breaks and coordinates their repair, so patients are very sensitive to radiation and develop ataxia, telangiectasias, infections and leukemia or lymphoma.