The Mre11͞Rad50 protein complex functions in diverse aspects of the cellular response to doublestrand breaks (DSBs), including the detection of DNA damage, the activation of cell cycle checkpoints, and DSB repair. Whereas genetic analyses in Saccharomyces cerevisiae have provided insight regarding DSB repair functions of this highly conserved complex, the implication of the human complex in Nijmegen breakage syndrome reveals its role in cell cycle checkpoint functions. We established mRad50 mutant mice to examine the role of the mammalian Mre11͞Rad50 protein complex in the DNA damage response. Early embryonic cells deficient in mRad50 are hypersensitive to ionizing radiation, consistent with a role for this complex in the repair of ionizing radiation-induced DSBs. However, the null mrad50 mutation is lethal in cultured embryonic stem cells and in early developing embryos, indicating that the mammalian Mre11͞Rad50 protein complex mediates functions in normally growing cells that are essential for viability.DNA damage is induced by extrinsic agents such as ionizing radiation and also arises spontaneously as an outcome of cellular processes such as DNA replication and oxidative metabolism. The cellular response to DNA damage involves the integration of pathways that detect and signal the presence of DNA damage, activate DNA damage-dependent cell cycle checkpoints, and mediate DNA repair. Genetic defects that impair any of these aspects of the cellular DNA damage response invariably lead to genomic instability. Studies in Saccharomyces cerevisiae and human cells have shown that the Mre11͞Rad50 protein complex functions in DNA damage detection and signaling as well as in the repair of DNA double-strand breaks (DSBs) (1-3). Hence, this highly conserved protein complex appears to play a central role in the cellular response to DSBs, linking DSB repair to cell cycle checkpoint functions.Genetic analyses indicate that in mitotic cells, the S. cerevisiae Mre11͞Rad50 protein complex functions in the repair of chromosomal DSBs through nonhomologous end joining (4-7). Mutations affecting the S. cerevisiae complex also lead to genomic instability in the form of increased chromosome loss and spontaneous loss of heterozygosity (i.e., allelic recombination) (2). In meiosis, the S. cerevisiae Mre11͞Rad50͞Xrs2 protein complex is critical to the initiation of meiotic recombination (8). In addition to these roles in DNA recombination and repair, recent data suggest that the S. cerevisiae Mre11͞ Rad50 protein complex also is linked to regulatory functions in the yeast cellular DNA damage response. Mutations in ScMRE11 suppress the inability of Yku70 mutants to overcome DSB-induced cell cycle arrest (9). Further, the response of Scrad50 mutants to hydroxyurea treatment suggests that the yeast Mre11͞Rad50 complex also may function in the activation of the S phase cell cycle checkpoint (10).Two recent observations link the human Mre11͞Rad50 complex to DSB recognition and the activation of cell cycle checkpoints. First, hMre11 lo...
Mre11, Rad50, and Nbs1 function in a protein complex that is central to the metabolism of chromosome breaks. Null mutants of each are inviable. We demonstrate here that hypomorphic Rad50 mutant mice (Rad50 S/S mice) exhibited growth defects and cancer predisposition. Rad50 S/S mice died with complete bone marrow depletion as a result of progressive hematopoietic stem cell failure. Similar attrition occurred in spermatogenic cells. In both contexts, attrition was substantially mitigated by p53 deficiency, whereas the tumor latency of p53 −/− and p53 +/− animals was reduced by Rad50 S/S . Indices of genotoxic stress and chromosomal rearrangements were evident in Rad50 S/S cultured cells, as well as in Rad50 S/S and p53 −/− Rad50 S/S lymphomas, suggesting that the Rad50 S/S phenotype was attributable to chromosomal instability. These outcomes were not associated with overt defects in the Mre11 complex's previously established double strand break repair and cell cycle checkpoint regulation functions. The data indicate that even subtle perturbation of Mre11 complex functions results in severe genotoxic stress, and that the complex is critically important for homeostasis of proliferative tissues.
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