Figure 5. Origin inhibition and activation in unperturbed cells and after replication stress.

a | Only approximately 10% of origins are typically used in an unperturbed cell cycle; most origins remain dormant and are replicated passively by replication forks emanating from adjacent origins. b | Stalled replication forks contain replication protein A (RPA)-coated single-stranded DNA that is sensed by the checkpoint kinase ataxia telangiectasia and RAD3-related protein (ATR), activating a signalling cascade (indicated by the beige star shape) that prevents initiation at late replication origins through checkpoint kinase 1 (CHK1)-mediated inhibition of phosphorylation events catalysed by cyclin-dependent kinases (CDKs) and DBF4-dependent kinase (DDK). Concomitantly, CHK1 activation permits replication initiation from origins (dormant or non-activated flexible origins) located near the stalled forks to complete DNA replication locally.