Etoposide induces the dispersal of DNA ligase I from replication factories

In eukaryotic cells DNA replication occurs in specific nuclear compartments , called replication factories, that undergo complex rearrangements during S-phase. The molecular mechanisms underlying the dynamics of replication fa ctories are still poorly defined. Here we show that etoposide, an anticance r drug that induces double-strand breaks, triggers the redistribution of DN A ligase I and proliferating cell nuclear antigen from replicative patterns and the ensuing dephosphorylation of DNA ligase I. Moreover, etoposide tri ggers the formation of RPA foci, distinct from replication factories. The e ffect of etoposide on DNA ligase I localization is prevented by aphidicolin , an inhibitor of DNA replication, and by staurosporine, a protein kinase i nhibitor and checkpoints' abrogator. We suggest that dispersal of DNA ligas e I is triggered by an intra-S-phase checkpoint activated when replicative forks meet topoisomerase II-DNA-cleavable complexes. However, etoposide tre atment of ataxia telangiectasia. cells demonstrated that ataxia-telangiecta sia-mutated activity is not required for the disassembly of replication fac tories and the formation of replication protein A foci.