Figure 2.

The cell response to HU-induced depletion of dNTPs during replication. Origins licensed on the DNA strand are grouped into replication “factories” the activation of which is strictly defined in time, from early- to late-replicating. In normal conditions, only a small percentage of origins will become activated and start to replicate DNA; the other origins remain dormant and will be replicated passively unless they are needed (A). If the currently replicating factory already has the desired amount of active forks, an ATR/Chk1 signaling mechanism limits dormant origin firing and also limits the activation of other factories that are supposed to replicate later (C). In the absence of free dNTPs (B), active forks stall and expose fragile ssDNA (B,C). ATR kinases stabilize stalled forks and also trigger the signaling pathway of the S-phase checkpoint, which arrests the cell cycle, inhibits origin firing in inactive factories, and restores RNR activity (C). The cell is unable to enter mitosis unless DNA replication is finished and any damage repaired (C).