Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products

Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recess ive genetic disorders with susceptibility to cancer and similar cellular ph enotypes(1). The protein product of the gene responsible for A-T, designate d ATM, is a member of a family of kinases characterized by a carboxy-termin al phosphatidylinositol 3-kinase-like domain(2,3). The NBS1 protein is spec ifically mutated in patients with Nijmegen breakage syndrome and forms a co mplex with the DNA repair proteins Rad50 and Mre11(4-7). Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytica lly active ATM. Complexes containing ATM and NBS1 exist in vivo in both unt reated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular respons e to DNA damage. This response includes S-phase checkpoint activation, form ation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity t o ionizing radiation. Together, these results demonstrate a biochemical lin k between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.