STEPTRACKERBIOCHEMISTRY + PATHOLOGY | MOLECULAR BIOLOGY | HIGH-YIELD REVIEW

DNA Mutations & Repair

Name the mutation by what it does to the protein, then match each repair pathway to the cancer syndrome that follows its failure.

FOCUS ON
Severity: silent < missense < nonsense; frameshift (not multiple of 3) usually truncates. Repair: NER = bulky UV dimers (xeroderma pigmentosum); BER = single damaged bases (glycosylase); MMR = replication mismatches (Lynch, microsatellite instability); NHEJ and HR = double-strand breaks (BRCA1/2, ataxia-telangiectasia, Fanconi).
MUTATION · PATHWAY
WHAT HAPPENS
DISEASE · EXAMPLE
CLUE
Silent
New codon codes the same amino acid (often third-base "wobble")
No change
Possible splice or speed effects only
Missense
New codon → different amino acid
Sickle cell (Glu → Val at β6)
Conservative if similar amino acid
Nonsense
New codon = stop → truncated protein
Some β-thalassemia, Duchenne
UAA, UAG, UGA stop codons
Frameshift
Insertion/deletion not divisible by 3 → downstream reading frame changes
Duchenne (severe) · Tay-Sachs (common allele)
In-frame deletion → milder (Becker)
Splice-site
Intron retained or exon skipped
Some β-thalassemia, Gaucher, cancers
—
Nucleotide excision repair
Endonucleases cut out a stretch around a bulky lesion (pyrimidine dimers), polymerase fills, ligase seals; G1 phase
Xeroderma pigmentosum (AR): extreme UV sensitivity, freckles, early skin cancers
Child with many skin cancers before age 10
Base excision repair
Glycosylase removes a damaged base (deamination, oxidation); AP endonuclease, lyase, polymerase β, ligase; throughout cell cycle
MUTYH-associated polyposis
Fixes spontaneous cytosine → uracil
Mismatch repair
Recognizes mispaired bases on the newly made strand (S/G2) and removes them
Lynch syndrome (MLH1, MSH2, MSH6, PMS2): colorectal (right-sided), endometrial, ovarian
Microsatellite instability
Nonhomologous end joining
Joins double-strand break ends without a template — error-prone
Ataxia-telangiectasia (ATM senses breaks), some SCID (Artemis, DNA-PK)
Also needed for V(D)J recombination
Homologous recombination
Uses the sister chromatid as template to fix double-strand breaks accurately (S/G2)
BRCA1/BRCA2 breast, ovarian, pancreatic, prostate; Fanconi anemia
PARP inhibitors (olaparib) kill BRCA-deficient cells
Chromosome instability syndromes
Defective DNA damage responses
Bloom (BLM helicase), Fanconi (crosslink repair → aplastic anemia), ataxia-telangiectasia
Sensitivity to radiation or crosslinkers

Mechanism — matching damage to repair

UV pyrimidine dimer
→
NERCut out oligonucleotide
One damaged baseDeamination, oxidation
→
BERGlycosylase
Replication mismatch
→
MMRNewly synthesized strand
Double-strand breakRadiation
→
NHEJ (quick, error-prone) or HR (accurate)

Repair defects → syndromes

PATHWAY
SYNDROME
CANCER / FEATURE
NER
Xeroderma pigmentosum
Skin SCC, BCC, melanoma
MMR
Lynch
Right colon, endometrium
BER
MUTYH polyposis
Colon polyps
HR
BRCA1/2, Fanconi
Breast, ovary; aplastic anemia
DSB sensing
Ataxia-telangiectasia
Ataxia, telangiectasia, IgA deficiency, lymphoma

How it's tested

COMMON CONFUSIONXeroderma pigmentosum is an NER defect (UV dimers); Lynch is MMR (mismatches). Both are inherited cancer syndromes but in different tissues.
THE TRAPDeletion of 3 nucleotides is an in-frame deletion (cystic fibrosis ΔF508), not a frameshift.
YOUR APPROACHCount the bases changed → effect on the reading frame → protein result. For repair, identify the damage type and the phase of the cell cycle.

If you see… think…

Child with severe sunburns and many skin cancers → xeroderma pigmentosum (NER)
Right-sided colon cancer at 40 + endometrial cancer in family → Lynch (MMR)
Tumor with microsatellite instability → mismatch repair defect
Breast + ovarian cancer, PARP inhibitor works → BRCA (homologous recombination)
Ataxia, telangiectasias, recurrent sinus infections → ataxia-telangiectasia (ATM)
Pancytopenia, absent thumbs, short stature → Fanconi anemia
Cytosine deaminated to uracil, fixed by glycosylase → base excision repair
Glu → Val substitution → missense (sickle cell)
Premature stop codon → nonsense mutation
Deletion of 3 bases removing one amino acid → in-frame (ΔF508)