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 gamma-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 [3H]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 [60Co] gamma-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 gamma-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 gamma-radiation in patients and healthy individuals could reflect the importance of PARP activity dependent on treatment with gamma-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.
Cristóvão
L
L
Department of Genetics, Faculty of Medical Sciences, New University of Lisbon, Portugal.
Lechner
M C
MC
Fidalgo
P
P
Leitão
C N
CN
Mira
F C
FC
Rueff
J
J
D011125:Adenomatous Polyposis Coli / Q000201:enzymology*; D000328:Adult; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000201:enzymology / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D009243:NAD / Q000097:blood; D011065:Poly(ADP-ribose) Polymerases / Q000097:blood*
D009243:NAD; D011065:Poly(ADP-ribose) Polymerases