SV40 T antigen interacts with Nbs1 to disrupt DNA replication control.
Nijmegen breakage syndrome (NBS) is characterized by radiation hypersensitivity, chromosomal instability, and predisposition to cancer. Nbs1, the NBS protein, forms a tight complex with Mre11 and Rad50, and these interactions contribute to proper double-strand break repair. The simian virus 40 (SV40) oncoprotein, large T antigen (T), also interacts with Nbs1, and T-containing cells experience chromosomal hyperreplication in a manner dependent on T/Nbs1 complex formation. A substantial fraction of NBS-deficient fibroblasts reinitiate DNA replication in discrete regions, and wild-type Nbs1 corrects this defect. Similarly, synthesis of an N-terminal Nbs1 fragment induced DNA rereplication and tetraploidy, in NBS-deficient but not NBS-proficient cells. Moreover, SV40 origin-containing DNA hyperreplicated in T-containing NBS-deficient cells by comparison with T-containing, Nbs1-reconstituted derivatives. Thus, Nbs1 suppresses rereplication of cellular DNA and SV40 origin-containing replicons, and T targets Nbs1, thereby enhancing the yield of new SV40 genomes during viral DNA replication.
Wu
Xiaohua
X
Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. xiaohwu@scripps.edu
Avni
Dror
D
Chiba
Takuya
T
Yan
Feng
F
Zhao
Qiping
Q
Lin
Yafang
Y
Heng
Henry
H
Livingston
David
D
D017766:Acid Anhydride Hydrolases; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D000076228:MRE11 Homologue Protein; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation; D011839:Radiation, Ionizing; D018741:Replication Origin; D014779:Virus Replication / Q000235:genetics
D000952:Antigens, Polyomavirus Transforming; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes