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. Author manuscript; available in PMC: 2022 Oct 21.
Published in final edited form as: Mol Cell. 2021 Sep 1;81(20):4243–4257.e6. doi: 10.1016/j.molcel.2021.08.009

Figure 7. Model depicting the basal-level activity of ATR in replication-fork surveillance and as a platform for replication-stress induced activation of the canonical ATR-Chk1 signaling.

Figure 7.

(A-B) Basal-level activity of ATR during normal replication: ATR monitor the level of RPA at replication forks via diffusion-controlled ATR-RPA contact, preventing RPA from accumulating at impeded forks via phosphorylation of Ser33 at RPA2.

(C) Gradual increase in global replication stress lead to the accumulation of RPA at forks, and the basal ATR-RPA contacts is amplified accordingly. This results in local crowding of ATR at the vicinity of forks. The formation of ATR concentration gradients around forks guarantees a high probability for the diffusion-mediated encounter of ATR with its activators at the fork, which drives the activation of the canonical ATR-Chk1 signaling.

(D) Schematic semi-quantitative illustration of the reaction coordinates for ATR-RPA interface at replication forks and its progression and expansion with increase replicative-stress, whereby the activation of the canonical ATR-Chk1 replication stress response emerges from the basal activity of ATR.