Figure 7.

A Model Describing ATR-Mediated Events in S Phase and Prophase at the Nuclear Envelope

The model integrates the observations deriving from yeast studies (Bermejo et al., 2011) focused on the S phase function of the ATR pathway, with the findings described in this paper. The nuclear envelope is shown in green; the chromosomes are shown in black; and the replicons are shown in yellow. The red bars at the envelope indicate the nuclear membrane areas exposed to mechanical stress. Briefly, nuclear envelope-associated chromatin transfers the mechanical forces arising from the topological transitions of replicating or condensing chromosomes to the nuclear envelope. Local nuclear membrane stress recruits ATR. The ATR response then coordinates chromosome replication and condensation with the nuclear envelope by modulating chromatin and nuclear envelope association. In ATR-defective cells, the inability to coordinate replication with the nuclear envelope at those chromatin regions associated to the lamin, causes fork collapse. The partially replicated chromatin remains in part associated to the NE when condensation begins, thus leading to progressive chromatin fragmentation and mitotic catastrophe.