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 cellular response to double-strand 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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-06, Vol.96 (13), p.7376-7381
Main Authors: Luo, Guangbin, Yao, Michelle S., Bender, Carla F., Mills, Michael, Bladl, Anthony R., Bradley, Allan, John H. J. Petrini
Format: Article
Language:English
Subjects:
Alleles
Animals
Biological Sciences
Blastocyst
Cell cycle
Cell Death
Cell growth
Cell lines
Cells
Deoxyribonucleic acid
DNA
DNA-Binding Proteins
Embryonic and Fetal Development - genetics
Embryonic and Fetal Development - radiation effects
Embryos
Endodeoxyribonucleases
Exodeoxyribonucleases
Exons
Fungal Proteins - genetics
Gene Expression Regulation, Developmental
Genetic mutation
Genetics
Giant cells
Humans
Ions
Mice
Mutation
Radiation
Saccharomyces cerevisiae Proteins
Stem Cells - pathology
Stem Cells - physiology
Yeast
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Summary:The Mre11/Rad50 protein complex functions in diverse aspects of the cellular response to double-strand 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 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 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 Mre11/Rad50 protein complex mediates functions in normally growing cells that are essential for viability.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.13.7376