In metazoan cells, inactivation or depletion of DDR factors, such as ATR, BRCA2, Chk1, Claspin, Rad51 or Wee1, leads to replication fork slowing and increased initiation density. Until now the mechanism by which these deficiencies modulate the replication dynamics has remained unclear, although a specific model has been proposed in the case of Chk1. However, the similarity in the phenotype observed in different DDR-deficient cells suggests to us that a common mechanism modulates the replication dynamics in all cases. We reasoned that a feature common to all DDR-deficient cells is that they are prone to accumulate DNA damages. On the other hand, DNA damages impact dNTPs biosynthesis in various organisms, which prompted us to determine whether the switch in replication dynamics observed in Chk1- and Rad51-deficient cells relies on damage signaling. Our results reconstitute, in two cell types, a signaling pathway that modulates the replication dynamics when DNA damage is present in S phase: DNA lesions ___>ATM/Chk2 ___> p53 ___> accumulation and chromatin recruitment of the repair-specific subunit of the ribonucleotide reductase (p53R2) ___> decreased availability of dNTPs for the replication machinery ___> replication fork slowing ___> passive activation of latent origins.
Relationship between DNA damage response and replication dynamics in mammals : role of the intra-S phase checkpoint