A worked example

Abstract

DNA replication must end without leaving unreplicated DNA, an active replisome on the product, or physical links that prevent daughter molecules from separating. These requirements create a distinct mechanical problem at the end of replication: the remaining parental duplex shrinks while torsional stress must be redistributed, replisomes enter one another's path, the final leading- and lagging-strand junctions must be converted into continuous DNA, and fork rotation can transfer intertwining into the replicated products. The solution is not one universal reaction. Programmed fork traps position terminal encounters in some bacterial chromosomes and episomes, origin firing and fork velocity generate broad encounter zones in many eukaryotic chromosomes, and rolling-circle or end-replicating systems terminate by strand transfer or processing of a physical DNA end. Nevertheless, these architectures can be compared as transformations of a terminal DNA substrate. Forks first reach a geometry that permits or requires remodeling; residual DNA synthesis and end processing then complete the nascent strands; in characterized yeast and metazoan systems, separate structural, biochemical, and extract studies support a model in which loss of fork DNA permits CMG ubiquitylation followed by Cdc48- or p97-dependent extraction; and topoisomerases or site-specific recombination remove direct links between products. Circular-template experiments directly expose covalent and topological product states; locus-resolved chromosomal assays can reveal incomplete or delayed synthesis. Failure therefore produces different pathologies depending on the interrupted transition, including renewed replication after bacterial fork fusion, persistent terminal gaps or replisomes, catenated products, and under-replicated DNA carried into mitosis. The central unresolved questions are the native structure of an unperturbed bacterial fork fusion, how final torsional stress is partitioned between the parental interval and daughter precatenanes, the minimal DNA change that licenses CMG removal, and the order of nascent-strand closure, replisome extraction, and product unlinking after the last parental interval disappears.