Figure 4.

Mechanisms of replication forks restart. During progression, a functional RF might encounter obstacles, which will generate replication stress as a result of, for example, single strand breaks, blocking lesions, or fork arrests (a). This lesion will trigger the slowing of the RF or, in worst case scenario, its stalling and collapse (b). Protection of stalled/collapse fork from nuclease degradation (d), might allow replication to complete by merging with a converging fork (e). Persistent collapse fork will require remodeling and processing to permit the restart of the replication (c). One key step is fork reversal/regression, forming a 4-branch structure commonly called “chicken foot”, which will protect from extensive nuclease degradation (d) but also mediates both DSB-dependent or DSB-free fork restart. Controlled resection of newly synthetized DNA on a reversed fork or stalled fork, and backtracking of the fork, form a 3′-protuding end, which coated with RAD51 can mediate D-loop formation and homology search to initiate a DSB-free HR restart (f). One-ended DSB can arise from encounter of single strand break with the replication machinery, but also from nuclease cleavage of persistent stalled fork or reversed fork (d). Such one-ended DSB are then taken in charge by BIR, a specialized homology-directed repair pathway (f). Other types of lesions, such as blocking lesions, can trigger DNA damage tolerance pathways, which permit the bypass of sources of replication stalling and comprise three main mechanisms (h). Translesion DNA synthesis (TLS) involves specific DNA polymerase able to traverse a blocking lesion. Template switching is the re-annealing of the nascent strand to sequence in the newly synthetized DNA. Repriming consists of reinitializing replication downstream of the blocking lesions (h). Fork restart is schematized by red lines and arrows.