The Mre11 complex — containing Mre11, Rad50 and Nbs1 — promotes the repair of double-strand DNA breaks (DSBs). One way to do this is by homologous recombination — a process that is intrinsically linked to DNA replication. Because of this connection, the Mre11 complex has been implicated in replication, and two new papers support this idea.

Jean Gautier and colleagues report in Molecular Cell the cloning and purification of the Xenopus Mre11 homologue. They show that X-Mre11 is phosphorylated in response to DSBs, and that this modification stimulates the 3′–5′ exonuclease activity of the X-Mre11 complex (the function of which is currently a mystery).

Gautier and colleagues asked whether X-Mre11 is phosphorylated in the absence of DSBs, using purified sperm nuclei that had been incubated in extracts to allow chromatin assembly and DNA replication. The authors detected phosphorylated X-Mre11 in the nuclear fraction during replication, indicating that active X-Mre11 can associate with chromatin during normal DNA synthesis. They then used several techniques to show that DSBs arise during replication, and that they accumulate when Mre11 is not present. The implication, they say, is that DSBs arise during normal replication and that the X-Mre11 complex is involved in their repair.

In Molecular and Cellular Biology, John Petrini and colleagues describe their investigations into the Nbs1 component of the Mre11 complex. Phosphorylation of Nbs1 is required for activation of the S-phase checkpoint, which stalls replication in response to DNA damage. However, cells containing an aberrant Nbs1 that lacks the amino terminus cannot activate the S-phase checkpoint, even when phosphorylated.

Given that the amino-terminal region of Nbs1 seems to be essential for checkpoint activation, Petrini and colleagues investigated it further using a two-hybrid screen and discovered that it interacts with the transcription factor E2F1. Within 400 base pairs of the Epstein–Barr virus latent origin of replication (oriP) are two E2F-binding sites, and the authors confirmed not only that E2F–Nbs1 binds near oriP, but also that binding increased as cells progressed through S phase. Finally they showed that the Mre11 complex co-localizes with DNA replication foci containing a replication protein — the proliferating cell nuclear antigen (PCNA) — throughout S phase. These results support the idea that the Mre11 complex influences the progression of S phase by acting not only at replication origins (through the interaction with E2F1) but also at the replication fork.