Fig. 5

Replication mechanisms. A Fork Stalling and Template Switching (FoSTeS) mechanism: (a) When a replication fork stalls, (b) the lagging strand disengages from its original template and, due to the presence of microhomology (purple), invades and switches to another template (dashed line) at another active replication fork and restarts DNA synthesis. (c) The nascent lagging strand can disengage again and invade other replication forks. Eventually, the strand can return to its original template and (a,d) restart synthesis. (e) The final product contains segments from different parts of the genome that were brought together due to microhomology. B Microhomology-Mediated Break-Induced Replication (MMBIR) mechanism: (a) A replication fork collapses when it encounters a DNA lesion, forming (b) a single-ended double-strand break. (c) A 5′–3′ resection creates a 3′ overhang with an exposed region of microhomology (purple), which serves as a template for (d) the invasion of a different region of the genome, where DNA synthesis is restarted. (e, f) The process can be repeated, and other regions of the genome can be invaded due to the presence of microhomology. (g) The final product presents a complex rearrangement with distinct parts of the genome united due to microhomology. In FoSTeS and MMBIR, the low processivity of the DNA polymerase leads to constant strand switching, especially at the beginning of the process, which may lead to short insertions in the junction points. As the invasion goes on, the DNA polymerase is switched and becomes more processive, allowing the replication to proceed until the end of the chromosome. The Break-Induced Replication (BIR) mechanism process is similar to MMBIR but uses larger homologous sequences instead of microhomologies