1. Molecular Biology and Genetics, Sloan-Kettering Institute, and
2. Pathology and Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, and
3. Weill-Cornell Graduate School of Medical Science, New York, New York 10021, USA

Correspondence to: John H. J. Petrini^1,3 Correspondence and requests for materials should be addressed to J.H.P. (Email: petrinij@mskcc.org).

The MRE11 complex (MRE11, RAD50 and NBS1) and the ataxia-telangiectasia mutated (ATM) kinase function in the same DNA damage response pathway to effect cell cycle checkpoint activation and apoptosis^{1, 2, 3}. The functional interaction between the MRE11 complex and ATM has been proposed to require a conserved C-terminal domain of NBS1 for recruitment of ATM to sites of DNA damage^{4, 5}. Human Nijmegen breakage syndrome (NBS) cells and those derived from multiple mouse models of NBS express a hypomorphic NBS1 allele that exhibits impaired ATM activity despite having an intact C-terminal domain^{3, 6, 7, 8, 9, 10, 11}. This indicates that the NBS1 C terminus is not sufficient for ATM function. We derived Nbs1^C/C mice in which the C-terminal ATM interaction domain is deleted. Nbs1^C/C cells exhibit intra-S-phase checkpoint defects, but are otherwise indistinguishable from wild-type cells with respect to other checkpoint functions, ionizing radiation sensitivity and chromosome stability. However, multiple tissues of Nbs1^C/C mice showed a severe apoptotic defect, comparable to that of ATM- or CHK2-deficient animals. Analysis of p53 transcriptional targets and ATM substrates showed that, in contrast to the phenotype of Chk2^-/- mice, NBS1^C does not impair the induction of proapoptotic genes. Instead, the defects observed in Nbs1^C/C result from impaired phosphorylation of ATM targets including SMC1 and the proapoptotic factor, BID.

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