DNA-DEPENDENT PROTEIN-KINASE ACTS UPSTREAM OF P53 IN RESPONSE TO DNA-DAMAGE

The tumour suppressor p53 becomes activated as a transcription factor in response to DNA damage(1-3), but the mechanism for this activation is unclear. A good candidate for an upstream activator of p53 is the D NA-dependent protein kinase (DNA-PK) that depends on the presence of D NA breaks for its activity(4-6). Here we investigate the link between DNA damage and the activation of DNA-PK and of p53. To determine wheth er DNA-PK is an upstream mediator of the p53 DNA-damage response, we a nalysed a severe combined-immunodeficiency (SCID) mouse cen Line, SCGR 11 (reb 7, 8), and the human glioma cell line M059J (ref. 9), Both cel l lines lack any detectable DNA-PK activity. We find that p53 is incap able of binding to DNA in the absence of DNA-PK, that DNA-PK is necess ary but not sufficient for activation of p53 sequence-specific DNA bin ding, and that this activation occurs in response to DNA damage. Our r esults establish DNA-PK as a link between DNA damage and p53 activatio n, and reveal the existence of a mammalian DNA-damage-response pathway .