Biochemistry chapters
DNA repair and its disorders
How DNA is damaged (spontaneous errors, UV light, radiation, chemicals), the types of mutation, the repair systems (mismatch, base excision, nucleotide excision, double-strand break repair) and the diseases caused when each fails: Lynch syndrome, xeroderma pigmentosum, ataxia-telangiectasia, BRCA cancers, Bloom and Fanconi.
- DNA is damaged by replication errors, spontaneous changes (deamination of cytosine to uracil, depurination), UV light (thymine (pyrimidine) dimers), ionising radiation (double-strand breaks) and chemicals; unrepaired changes become mutations (silent, missense as in sickle cell, nonsense making a stop codon, frameshift from insertions or deletions not in multiples of three).
- Repair systems and their diseases: mismatch repair (MLH1, MSH2) → Lynch syndrome (HNPCC); base excision repair (glycosylases remove damaged bases such as uracil); nucleotide excision repair (removes bulky lesions such as thymine dimers) → xeroderma pigmentosum; double-strand break repair by homologous recombination (BRCA1/2) or non-homologous end joining → BRCA cancers, ataxia-telangiectasia (ATM), Fanconi anaemia.
- p53 senses damage and halts the cell cycle at G1/S for repair or triggers apoptosis.
On this page
Causes of DNA damage
| Cause | Damage |
|---|---|
| Replication errors | Wrong base inserted (mismatch) |
| Spontaneous chemical change | Deamination (cytosine → uracil; 5-methylcytosine → thymine), depurination (loss of purine bases), oxidation by free radicals |
| Ultraviolet light (UVB) | Pyrimidine (thymine) dimers: adjacent pyrimidines become covalently linked, distorting the helix |
| Ionising radiation (X-rays, gamma rays) | Double-strand breaks, free radicals |
| Chemicals | Alkylating agents (cancer drugs, nitrosamines), aflatoxin, benzo[a]pyrene (tobacco), intercalating agents (frameshifts) |
Types of mutation
| Type | Change | Effect | Example |
|---|---|---|---|
| Silent | One base changed, same amino acid (code is degenerate; usually the third base) | None | (none specific) |
| Missense | One base changed → different amino acid | Variable | Sickle cell disease: GAG → GTG, glutamate → valine at position 6 of β-globin |
| Nonsense | One base changed → stop codon | Shortened, usually non-functional protein | Some β⁰-thalassaemias, Duchenne muscular dystrophy |
| Frameshift | Insertion or deletion not in multiples of three | Reading frame shifts → garbled protein, often early stop | Duchenne muscular dystrophy, Tay-Sachs |
| In-frame deletion | Deletion of three bases | Loses one amino acid | Cystic fibrosis ΔF508 (loss of phenylalanine at position 508) |
| Splice-site | Change at an intron-exon boundary | Abnormal splicing | Some β-thalassaemias |
| Trinucleotide repeat expansion | Repeated triplets grow | Anticipation | Fragile X, Huntington disease |
- Transition: purine to purine or pyrimidine to pyrimidine (A↔G, C↔T).
- Transversion: purine to pyrimidine or the reverse.
Sickle cell = missense (Glu6Val). Cystic fibrosis ΔF508 = in-frame deletion of three bases. Duchenne = frameshift deletions (Becker = in-frame, milder).
DNA repair systems
1. Mismatch repair
- Fixes mismatched bases left after replication, in the G2 phase. The repair proteins find the newly made strand and replace the wrong section.
- Genes: MLH1, MSH2, MSH6, PMS2.
- Defect → Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC): autosomal dominant; colorectal (often right-sided), endometrial, ovarian, gastric and urinary tract cancers at young ages; tumours show microsatellite instability.
2. Base excision repair
- Removes single damaged bases (for example uracil from cytosine deamination, oxidised or alkylated bases), mainly in the G1 phase.
- Steps: DNA glycosylase (uracil-DNA glycosylase) removes the base → AP endonuclease cuts the backbone at the empty (apurinic/apyrimidinic) site → DNA polymerase β fills the gap → ligase seals it.
- Why DNA uses thymine, not uracil: any uracil in DNA must have come from damaged cytosine, so it can be recognised and removed.
3. Nucleotide excision repair
- Removes bulky lesions that distort the helix, especially thymine (pyrimidine) dimers from UV light, and adducts from benzo[a]pyrene.
- Steps: endonuclease cuts the damaged strand on both sides → a short stretch of nucleotides is removed → DNA polymerase fills the gap → ligase seals it.
- Defect → xeroderma pigmentosum: autosomal recessive; extreme sun sensitivity, freckling, dry skin, eye damage, and skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma) from childhood; some have neurological problems. Strict sun protection is essential.
4. Double-strand break repair
- Homologous recombination: uses the sister chromatid as a template, so it is accurate; works in S and G2 phases. Involves BRCA1, BRCA2 and ATM. Defects → hereditary breast and ovarian cancer; such tumours respond to PARP inhibitors (olaparib).
- Non-homologous end joining: joins broken ends directly, without a template; quick but error-prone; also used to join antibody and T-cell receptor gene segments (defects can cause some forms of SCID).
Other repair disorders
| Disorder | Defect | Features |
|---|---|---|
| Ataxia-telangiectasia | ATM (senses double-strand breaks) | Cerebellar ataxia, telangiectasia of eyes and skin, immunodeficiency (IgA deficiency), radiosensitivity, lymphoma and leukaemia, raised AFP |
| Bloom syndrome | BLM helicase | Short stature, sun-sensitive facial rash, immunodeficiency, many cancers |
| Fanconi anaemia | Repair of interstrand cross-links | Aplastic anaemia, thumb and radius anomalies, short stature, café-au-lait spots, leukaemia; sensitive to cross-linking drugs |
| Li-Fraumeni syndrome | TP53 (inherited) | Many cancers at young ages (sarcomas, breast, brain, adrenal, leukaemia) |
| Werner syndrome | WRN helicase | Premature ageing in adults |
XP = nucleotide excision (UV, thymine dimers). Lynch = mismatch. BRCA = homologous recombination. Ataxia-telangiectasia = ATM (radiation sensitivity).
p53: guardian of the genome
p53 detects DNA damage and:
- Stops the cell cycle at G1/S (through p21) to allow repair;
- activates repair genes;
- triggers apoptosis (through BAX) if damage is beyond repair.
Loss of p53 lets damaged cells keep dividing; TP53 is the most commonly mutated gene in human cancers. See carcinogenesis.
Expect: causes of DNA damage, types of mutation with examples (sickle cell missense, ΔF508, Duchenne frameshift), transitions vs transversions, the four repair systems and their enzymes, xeroderma pigmentosum (nucleotide excision, UV, thymine dimers), Lynch syndrome (mismatch repair, microsatellite instability), BRCA and homologous recombination, ataxia-telangiectasia, Fanconi anaemia, why DNA has thymine, and the role of p53.
Quick revision
- UV → thymine dimers → nucleotide excision repair (xeroderma pigmentosum).
- Replication mismatches → mismatch repair (Lynch syndrome, MLH1/MSH2).
- Single damaged bases (uracil) → base excision repair (glycosylase, AP endonuclease).
- Double-strand breaks → homologous recombination (BRCA1/2) or end joining.
- Ataxia-telangiectasia: ATM, radiosensitivity, IgA deficiency.
- Sickle cell: missense Glu6Val. Cystic fibrosis: ΔF508 in-frame deletion.
- p53: G1/S arrest, repair or apoptosis.
Written by The House Job from standard biochemistry references (Lippincott Illustrated Reviews: Biochemistry).
FAQ
Which DNA repair system is defective in xeroderma pigmentosum?
Nucleotide excision repair, which normally removes thymine dimers caused by ultraviolet light.
Which repair defect causes Lynch syndrome?
Defective mismatch repair (genes such as MLH1 and MSH2), which causes microsatellite instability.
What kind of mutation causes sickle cell disease?
A missense mutation that replaces glutamate with valine at position 6 of the β-globin chain.
Why does DNA contain thymine instead of uracil?
Cytosine can spontaneously deaminate to uracil; using thymine lets repair enzymes recognise any uracil in DNA as damage and remove it.