Regulation of Claspin by the p38 stress-activated protein kinase protects cells from DNA damage

Stress-activated protein kinases (SAPKs) enhance survival in response to environmental changes. In yeast, the Hog1 SAPK and Mrc1, a protein required for DNA replication, define a safeguard mechanism that allows eukaryotic cells to prevent genomic instability upon stress during S-phase. Here we show that, in mammals, the p38 SAPK and Claspin—the functional homolog of Mrc1—protect cells from DNA damage upon osmostress during S-phase. We demonstrate that p38 phosphorylates Claspin and either the mutation of the p38-phosphorylation sites in Claspin or p38 inhibition suppresses the protective role of Claspin on DNA damage. In addition, wild-type Claspin but not the p38-unphosphorylatable mutant has a protective effect on cell survival in response to cisplatin treatment. These findings reveal a role of Claspin in response to chemotherapeutic drugs. Thus, this pathway protects S-phase integrity from different insults and it is conserved from yeast to mammals. [Display omitted] •p38 and Claspin prevent stress-induced DNA damage in mammals as Hog1 and Mrc1 do in yeast•p38 and the DNA damage checkpoint drive Claspin phosphorylation on different sites•p38 SAPK phosphorylation of Claspin protects cells from DNA damage during S-phase•The p38 sites in Claspin are relevant to promote resistance to cisplatin treatment Preventing collisions between the RNA and DNA polymerases during replication is essential to maintain genomic integrity. Here, Ulsamer et al. report that a mechanism involving the p38 SAPK and Claspin, which is conserved from yeast to humans, prevents DNA damage upon stress during S-phase.