The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder

We show that hypomorphic mutations in hMRE11, but not in ATM, are present i n certain individuals with an ataxia-telangiectasia-like disorder (ATLD). T he cellular features resulting from these hMRE11 mutations are similar to t hose seen in A-T as well as NBS and include hypersensitivity to ionizing ra diation, radioresistant DNA synthesis, and abrogation of ATM-dependent even ts, such as the activation of Jun kinase following exposure to gamma irradi ation. Although the mutant hMre11 proteins retain some ability to interact with hRad50 and Nbs1, formation of ionizing radiation-induced hMre11 and Nb s1 fool was absent in hMRE11 mutant cells. These data demonstrate that ATM and the hMre11/h Rad50/Nbs1 protein complex act in the same DNA damage resp onse pathway and link hMre11 to the complex pathology of A-T.