MOLECULAR AND CELLULAR BIOLOGY,

We show that the Mre11 complex associates with E2F family members via the Nbs1 N terminus. This asso-ciation and Nbs1 phosphorylation are correlated with S-phase checkpoint proficiency, whereas neither is suf-ficient individually for checkpoint activation. The Nbs1 E2F interaction occurred near the Epstein-Barr virus origin of replication as well as near a chromosomal replication origin in the c-myc promoter region and was re-stricted to S-phase cells. The Mre11 complex colocalized with PCNA at replication forks throughout S phase, both prior to and coincident with the appearance of nascent DNA. These data suggest that the Mre11 complex sup-presses genomic instability through its influence on both the regulation and progression of DNA replication. The Mre11 complex (composed of Mre11, Rad50, and Nbs1) and the ataxia-telangiectasia mutated (ATM) protein kinase are required to activate a DNA damage-induced S-phase checkpoint in mammalian cells (46). Mutations in the ATM, MRE11, or NBS1 gene (from patients with ataxia-telan-giectasia [A-T], ataxia-telangiectasia-like disorder [A-TLD], or Nijmegen breakage syndrome [NBS], respectively) abrogate this checkpoint (12, 52, 58, 66). Mutant cells fail to repress th