Mre11 Complex and DNA Replication: Linkage to E2F and Sites of DNA Synthesis

Abstract

We show that the Mre11 complex associates with E2F family members via the Nbs1 N terminus. This association and Nbs1 phosphorylation are correlated with S-phase checkpoint proficiency, whereas neither is sufficient 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 restricted 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 suppresses genomic instability through its influence on both the regulation and progression of DNA replication.

ACKNOWLEDGMENTS

We thank D. Eick for the gift of Raji 525-7 cells, T. de Lange for helpful discussion and comments, and Allen Edmonds for critical insight.

This work was supported by the Milwaukee Foundation (J.H.J.P.), the National Institutes of Health (GM59413 to J.H.J.P., CA09681 to J.W.), the Department of Energy (J.H.J.P.), and the Public Health Service (CA45240 to P.J.F.).