The many interfaces of Mre11.

This year, the Mre11 complex has attracted a new group of aficionados interested in cancer and in checkpoint regulation. In humans, the p95 component is mutated in Nijmegen breakage syndrome (NBS), a condition that has similarities with ataxia telangiectasia, including ionizing radiation-sensitivity, cancer predisposition, and a failure to arrest at G1/S in response to DNA damage (5xCarney, J.P, Maser, R.S, Olivares, H, Davis, E.M, Le Beau, M, Yates, J.R III, Hays, L, Morgan, W.F, and Petrini, J.H. Cell. 1998; 93: 477–486Abstract | Full Text | Full Text PDF | PubMed | Scopus (858)See all References, 26xVaron, R, Vissinga, C, Platzer, M, Cerosaletti, K.M, Chrzanowska, K.H, Saar, K, Beckmann, G, Seemanova, E, Cooper, P.R, Nowak, N.J et al. Cell. 1998; 93: 467–476Abstract | Full Text | Full Text PDF | PubMed | Scopus (725)See all References). Possibly, Mre11/Rad50/NBS binds to DSB ends and signals the presence of that damage.An alternative possibility is that the signal of DNA damage is the extent of single-stranded DNA produced by the exonuclease activity of the Mre11 complex. In Saccharomyces, evidence supporting this idea has come not from studying the ability of cells to arrest after DNA damage, but from their capacity to adapt and resume growth when damage persists. Two DSBs are sufficient to discourage a wild-type yeast cell from adapting to checkpoint-induced G2/M arrest, but this permanent arrest is suppressed by an mre11 or rad50 deletion that reduces the extent of single-stranded DNA (Lee et al. 1998xLee, S.-E, Moore, J.K, Holmes, A, Umezu, K, Kolodner, R, and Haber, J.E. Cell. 1998; 94: 399–409Abstract | Full Text | Full Text PDF | PubMed | Scopus (520)See all ReferencesLee et al. 1998).There is no doubt that Mre11p is attracted to the sites of DNA damage, for repair and possibly as part of the damage-signaling apparatus. Following irradiation, foci containing both Mre11p and Rad50p have been seen in mammalian cells and in yeast. A stunning series of micrographs illustrating this point were published by Nelms et al. 1998xNelms, B.E, Maser, R.S, MacKay, J.F, Lagally, M.G, and Petrini, J.H. Science. 1998; 280: 590–592Crossref | PubMed | Scopus (376)See all ReferencesNelms et al. 1998, who examined mammalian nuclei irradiated with ultrasoft X-rays passed through a grid that produced stripes of DNA damage. The remarkable finding was not that hMre11p was localized within the irradiated regions, but that in repair-defective cells these stripes persisted for hours, suggesting that the damaged DNA was not diffusing around the nucleus. Interestingly, these foci do not attract Rad51p. If DNA ends were being resected, then the 3′-ended single-stranded regions ought to be attractive sites for the assembly of Rad51p filaments that is the first step in repairing DSBs by homologous recombination. However, no such foci containing both hMre11p and hRad51p were seen. A similar lack of colocalization has been seen in yeast cells that cannot complete meiosis and in irradiated mitotic cells (Usui et al. 1998xUsui, T, Ohta, T, Oshiumi, H, Tomizawa, J, Ogawa, H, and Ogawa, T. Cell. 1998; 95: 705–716Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesUsui et al. 1998).The Mre11 complex is attracted to DSBs and can participate in several different pathways of repair and recombination. It remains “only” to figure out how Mre11p, Rad50p, Xrs2p, and the proteins with which they interact enable the cell to perform these many tasks. Given that almost half the papers on Mre11p have been published in 1998, it is likely we will soon learn much more about the many facets of this multitalented protein.