DNA Replication, Mutation, and Genome Stability
Replication as a fidelity-limited process
Polymerase chemistry and origin control
DNA replication requires helicases, primases, polymerases, sliding clamps, ligases, and topoisomerases. Origin licensing and timing prevent re-replication, while fork protection mechanisms maintain stability under replication stress.
Mutation classes
Sources of mutational variation
Mutations arise from replication errors, spontaneous chemical changes such as deamination, DNA damage from reactive oxygen species, ultraviolet light, ionizing radiation, and mobile genetic elements. The observed spectrum is strongly shaped by repair efficiency, chromatin context, and local sequence composition.
Conceptual point
Mutation is not random in effect, but it is often approximately random with respect to immediate adaptive need. Mutation rates and spectra are highly structured by molecular mechanisms.
Major DNA repair pathways
| Pathway | Typical lesion | Typical outcome |
|---|---|---|
| Mismatch repair | Replication misincorporation | Restores base-pairing fidelity |
| Base excision repair | Small base damage | Removes altered bases and fills gap |
| Nucleotide excision repair | Bulky adducts and UV lesions | Excises damaged segment |
| Homologous recombination | Double-strand breaks and collapsed forks | Accurate repair using homologous template |
| Non-homologous end joining | Double-strand breaks | Fast but often error-prone repair |
Why are homologous recombination and non-homologous end joining considered distinct repair pathways?
Homologous recombination uses a related template and is generally more accurate, whereas non-homologous end joining ligates DNA ends directly and is more error-prone.
Correct answer: They differ primarily in whether they use a homologous template and in fidelity
What is the biological significance of DNA mismatch repair failure?
Loss of mismatch repair permits replication errors to accumulate, particularly in repetitive DNA.
Correct answer: It increases the mutation rate, often producing microsatellite instability and elevated risk of disease such as cancer.
How a replication fork fails
-
1
A lesion or hard-to-replicate region stalls the fork.
-
2
Single-stranded DNA accumulates and activates checkpoint signaling.
-
3
Fork reversal, translesion synthesis, or recombination-mediated rescue may occur.
-
4
If rescue fails, collapse leads to double-strand breaks and genome instability.
Which class of lesion is most directly associated with UV light exposure?
UV light commonly induces pyrimidine dimers, especially thymine dimers and related photoproducts.
Correct answer: Cyclobutane pyrimidine dimers