The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage.
The Nijmegen breakage syndrome (NBS), a chromosomal instability disorder, is characterized in part by cellular hypersensitivity to ionizing radiation. Repair of DNA double-strand breaks by radiation is dependent on a multifunctional complex containing Rad50, Mre11, and the NBS1 gene product, p95 (NBS protein, nibrin). The role of p95 in these repair processes is unknown. Here it is demonstrated that Mre11 is hyperphosphorylated in a cell cycle-independent manner in response to treatment of cells with genotoxic agents including gamma irradiation. This response is abrogated in two independently established NBS cell lines that have undetectable levels of the p95 protein. NBS cells are also deficient for radiation-induced nuclear foci containing Mre11, while those with Rad51 are unaffected. An analysis of the kinetic relationship between Mre11 phosphorylation and the appearance of its radiation-induced foci indicates that the former precedes the latter. Together, these data suggest that specific phosphorylation of Mre11 is induced by DNA damage, and p95 is essential in this process, perhaps by recruiting specific kinases.
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245, USA.
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D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D019457:Chromosome Breakage; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism; D005720:Gamma Rays; D006801:Humans; D007700:Kinetics; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; D010766:Phosphorylation; D029701:Saccharomyces cerevisiae Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; C086930:RAD50 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D004720:Endonucleases; D000076228:MRE11 Homologue Protein