53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer.
53BP1 is a conserved nuclear protein that is implicated in the DNA damage response. After irradiation, 53BP1 localizes rapidly to nuclear foci, which represent sites of DNA double strand breaks, but its precise function is unclear. Using small interference RNA (siRNA), we demonstrate that 53BP1 functions as a DNA damage checkpoint protein. 53BP1 is required for at least a subset of ataxia telangiectasia-mutated (ATM)-dependent phosphorylation events at sites of DNA breaks and for cell cycle arrest at the G2-M interphase after exposure to irradiation. Interestingly, in cancer cell lines expressing mutant p53, 53BP1 was localized to distinct nuclear foci and ATM-dependent phosphorylation of Chk2 at Thr 68 was detected, even in the absence of irradiation. In addition, Chk2 was phosphorylated at Thr 68 in more than 50% of surgically resected lung and breast tumour specimens from otherwise untreated patients [corrected]. We conclude that the constitutive activation of the DNA damage checkpoint pathway may be linked to the high frequency of p53 mutations in human cancer, as p53 is a downstream target of Chk2 and ATM.
DiTullio
Richard A
RA
Wistar Institute, Philadelphia, PA 19104-4268, USA.
Mochan
Tamara A
TA
Venere
Monica
M
Bartkova
Jirina
J
Sehested
Maxwell
M
Bartek
Jiri
J
Halazonetis
Thanos D
TD
D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C498301:TP53BP1 protein, human; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases