Absence of stimulation of poly(ADP-ribose) polymerase activity in patients predisposed to colon cancer

Poly(ADP-ribose)polymerase (PARP) has been implicated in DNA repair mechanisms and the associated activity shown to markedly increase after DNA damage in carcinogen-treated cells. A defective DNA repair has been associated to the aetiology of human cancers. In order to assess the potential role of this enzyme in cellular response to DNA damage by γ-radiation, we studied the activity of PARP in patients with familial adenomatous polyposis (FAP). We compared poly(ADP-ribose)polymerase activity by the rate of incorporation of radioactivity from [ ³ H]adenine-NAD ⁺ into acid-insoluble material in permeabilized leucocytes from FAP patients and healthy volunteers. Concomitantly, the intracellular levels of NAD ⁺ - the substrate for the PARP - and the reduced counterpart NADH were determined using an enzymatic cycling assay 30 min after [ ⁶⁰ Co] γ-ray cells irradiation. Our results demonstrate that a marked stimulation of PARP activity is produced upon radiation of the cells from healthy subjects but not in the FAP leucocytes, which concomitantly show a marked decrease in total NAD ⁺ /NADH content. Our observations point to a role of PARP in the repair of the γ-radiation-induced DNA lesions through a mechanism that is impaired in the cells from FAP patients genetically predisposed to colon cancer. The differences observed in PARP activation by γ-radiation in patients and healthy individuals could reflect the importance of PARP activity dependent on treatment with γ-rays. The absence of this response in FAP patients would seem to suggest a possible defect in the role of PARP in radiation-induced DNA repair in this cancer-prone disease.