Identification of Early Replicating Fragile Sites that Contribute to Genome Instability
Menée in vitro et à l'aide de 203 échantillons prélevés sur des patients atteints d'un lymphome à grandes cellules B, cette étude identifie sur l'ADN des sites fragiles de réplication précoce associés à une instabilité génomique
DNA double-strand breaks (DSBs) in B lymphocytes arise stochastically during replication or as a result of targeted DNA damage by activation-induced cytidine deaminase (AID). Here we identify recurrent, early replicating, and AID-independent DNA lesions, termed early replication fragile sites (ERFSs), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFSs colocalize with highly expressed gene clusters and are enriched for repetitive elements and CpG dinucleotides. Although distinct from late-replicating common fragile sites (CFS), the stability of ERFSs and CFSs is similarly dependent on the replication-stress response kinase ATR. ERFSs break spontaneously during replication, but their fragility is increased by hydroxyurea, ATR inhibition, or deregulated c-Myc expression. Moreover, greater than 50% of recurrent amplifications/deletions in human diffuse large B cell lymphoma map to ERFSs. In summary, we have identified a source of spontaneous DNA lesions that drives instability at preferred genomic sites. º Early replicating fragile sites (ERFSs) break spontaneously during replication º ERFSs translocate to AID-induced breaks º Recurrent genomic aberrations in B cell lymphomas map to ERFSs º ERFSs are distinct from late replicating common fragile sites Many recurrent mutations in B cell lymphomas are not associated with AID activity; the genomic instability is instead caused by recurrent fragile genomic loci that are damaged during replication, which may then translocate to AID-induced breaks.