FIGURE 2.

Initiation and outcomes of Replication Fork Stalling at chromosomal ends. Replication forks could stall just upstream to or on telomeric repeat tracts due to different obstacles. Hampering of replication fork progression may be caused by an incapacity of DNA unwinding by replicative helicases (block 1), a situation expected in the context of topological barriers (gray rectangle on the figure). Tightly bound proteins, compacted telomeric chromatin, and nuclear envelope anchoring are strong topological barriers at chromosomal ends. In humans, the unusual DNA structure of the t-loop could also induce a topological stress in front of the replication fork. At least two other situations could induce replication fork stalling with lesions inhibiting only leading strand synthesis (block 2) or lagging strand synthesis (block 3). Given that G4s could be formed on the G-rich strand (blue line) during lagging strand synthesis, a lagging strand specific defect could be expected with this kind of replication stress. In contrast, t-loops or DNA/RNA hybrids could lead to leading strand synthesis defects. Depending on the kind of replication stress encountered, there are various pathways to deal with the consequences of a stalled replication fork. Replication restart can occur by alleviation of the replication stress and repriming events. Replication fork remodeling with fork reversal could also follow replication fork stalling. In addition, complete collapse of the replication fork could occur, resulting in DSBs or one-sided DSBs that initiate appropriate or inappropriate repair pathways.