DNA Replication, Repair, and Genome Stability
Replication as a High-Fidelity Process
Semiconservative copying and coordination
DNA replication is semiconservative and highly coordinated across leading and lagging strands. Replication forks integrate helicases, primases, polymerases, sliding clamps, ligases, topoisomerases, and accessory factors. Fidelity arises from base selection, polymerase proofreading, and post-replicative mismatch repair, yielding error rates far below those expected from chemistry alone.
What is the main function of a sliding clamp?
Sliding clamps tether polymerases to DNA, reducing dissociation and increasing processivity.
Correct answer: To increase polymerase processivity
Why are telomeres necessary in linear chromosomes?
Without telomeric protection, natural ends can be mistaken for DNA breaks.
Correct answer: They protect chromosome ends from degradation and end-to-end fusion and help solve the end-replication problem.
Damage and Repair Pathways
Genome maintenance systems
Cells encounter DNA lesions from replication errors, UV light, ionizing radiation, reactive oxygen species, and chemical mutagens. Repair pathways include mismatch repair, base excision repair, nucleotide excision repair, homologous recombination, and non-homologous end joining. The choice among pathways depends on lesion type, cell-cycle stage, and chromatin context. Failure of repair generates mutational signatures, chromosomal rearrangements, and genome instability that can drive cancer and developmental disorders.
Which repair pathway is most associated with high-fidelity repair of double-strand breaks using a homologous template?
Homologous recombination uses an intact homologous sequence as a template and is generally error-minimizing.
Correct answer: Homologous recombination
Why can defective mismatch repair increase microsatellite instability?
Microsatellites are especially vulnerable to polymerase slippage.
Correct answer: Because replication slippage in repetitive regions is not corrected efficiently, leading to insertion-deletion mutations.