Christine Eischen
Faculty Member
Last active: 1/20/2015

Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair.

Alt JR, Bouska A, Fernandez MR, Cerny RL, Xiao H, Eischen CM
J Biol Chem. 2005 280 (19): 18771-81

PMID: 15734743 · DOI:10.1074/jbc.M413387200

Mdm2 directly regulates the p53 tumor suppressor. However, Mdm2 also has p53-independent activities, and the pathways that mediate these functions are unresolved. Here we report the identification of a specific association of Mdm2 with Mre11, Nbs1, and Rad50, a DNA double strand break repair complex. Mdm2 bound to the Mre11-Nbs1-Rad50 complex in primary cells and in cells containing inactivated p53 or p14/p19ARF, a regulator of Mdm2. Further analysis revealed that Mdm2 directly bound to Nbs1 but not to Mre11 or Rad50. Amino acids 198-314 of Mdm2 were required for Mdm2/Nbs1 association, and neither the N terminus forkhead-associated and breast cancer C-terminal domains nor the C terminus Mre11 binding domain of Nbs1 mediated the interaction of Nbs1 with Mdm2. Mdm2 co-localized with Nbs1 to sites of DNA damage following gamma-irradiation. Notably, Mdm2 overexpression inhibited DNA double strand break repair, and this was independent of p53 and ARF, the alternative reading frame of the Ink4alocus. The delay in DNA repair imposed by Mdm2 required the Nbs1 binding domain of Mdm2, but the ubiquitin ligase domain in Mdm2 was dispensable. Therefore, Nbs1 is a novel p53-independent Mdm2 binding protein and links Mdm2 to the Mre11-Nbs1-Rad50-regulated DNA repair response.

MeSH Terms (34)

Acid Anhydride Hydrolases Amino Acid Sequence Animals Blotting, Western Cell Cycle Proteins Cell Line Cell Line, Tumor DNA, Complementary DNA-Binding Proteins DNA Damage DNA Repair DNA Repair Enzymes Gamma Rays Glutathione Transferase HeLa Cells Humans Immunoprecipitation K562 Cells Mice Mice, Transgenic Microscopy, Fluorescence Molecular Sequence Data MRE11 Homologue Protein Mutation NIH 3T3 Cells Nuclear Proteins Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins Proto-Oncogene Proteins c-mdm2 Sequence Homology, Amino Acid Silver Staining Time Factors Tumor Suppressor Protein p53

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