Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation

The Mre11/Rad50 protein complex functions in diverse aspects of the cellula r response to double-strand breaks (DSBs), including the detection of DNA d amage, the activation of cell cycle checkpoints, and DSB repair. Whereas ge netic analyses in Saccharomyces cerevisiae have provided insight regarding DSB repair functions of this highly conserved complex, the implication of t he human complex in Nijmegen breakage syndrome reveals its role in cell cyc le checkpoint functions. We established mRad50 mutant mice to examine the r ole of the mammalian,Mre11/Rad50 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 ionizin g radiation-induced DSBs, However, the null mrad50 mutation is lethal in cu ltured embryonic stem cells and in early developing embryos, indicating tha t the mammalian,Mre11/Rad50 protein complex mediates functions in normally growing cells that are essential for viability.