Semi-conservative, bidirectional, with leading and lagging strands
Expansion
- Semi-conservative: each daughter molecule keeps one parental strand
- Helicase unwinds; single strand binding proteins stabilise; topoisomerase relieves supercoiling
- Primase lays an RNA primer, since polymerase cannot start de novo
- DNA polymerase extends only 5-prime to 3-prime
- Leading strand: continuous
- Lagging strand: discontinuous Okazaki fragments, later joined by ligase
- Proofreading by 3-prime to 5-prime exonuclease activity gives high fidelity
Telomeres shorten with each division because the lagging strand cannot be completed to the very end (the end replication problem). Telomerase replenishes them in stem cells, germ cells and most cancers, and telomere shortening contributes to cellular senescence.
Drug targets: fluoroquinolones inhibit bacterial DNA gyrase (a topoisomerase); etoposide and doxorubicin target human topoisomerases; and many chemotherapy agents act during S phase.
Defects in repair cause characteristic syndromes: xeroderma pigmentosum (nucleotide excision repair), Lynch syndrome (mismatch repair), and BRCA-related cancers (homologous recombination), the last exploited therapeutically by PARP inhibitors.