Differential modulation of Ku70/80 DNA-binding activity in a patient with multiple basal cell carcinomas.
Ku70/80 nonhomologous end-joining activity is essential for resolving random DNA double-strand breaks, and the Ku70/80 protein complex has been proposed as "caretaker" of genomic stability. We studied the Ku70/80 heterodimer activity in a patient affected by multiple basal cell carcinomas with a personal history of moderate exposure to ionizing radiation. The Ku70/80 DNA-binding activity was analyzed, by electrophoretic mobility shift assay, in five tumor biopsies from different sites and at distinct clinical stages, and in three matched normal skin samples from the same patient. As control normal tissues from healthy individuals were also tested. The five basal cell carcinomas were classified as "non aggressive" and "aggressive" on the basis of morphologic parameters and expression of the molecular markers bcl-2, Ki67/MIB1, and p53. A 62% increase in the Ku70/80 DNA-binding activity was found in normal skin from the patient, compared to unexposed individuals (p<0.0001). The nuclear activity of the heterodimer was further increased in nonaggressive basal cell carcinomas compared to both matched normal skin from the patient (31%, p=0.0001) and tissues from healthy controls (73%, p=0.0001). Strikingly, the two aggressive basal cell carcinomas tested showed very low Ku70/80 DNA-binding activity with a reduction of 87% compared to normal skin from the patient (p<0.0001) and 64% compared to controls (p=0.001). Although these results are limited to only one patient, together with other recent studies they support the hypothesis that downregulation of the nonhomologous end-joining pathway may be associated with tumor progression.
Mazzarelli
Paola
P
Laboratory for Molecular Medicine and Biotechnology, Interdisciplinary Center for Biomedical Research, Università Campus Bio-Medico, Rome, Italy.
Rabitti
Carla
C
Parrella
Paola
P
Seripa
Davide
D
Persichetti
Paolo
P
Marangi
Giovanni Francesco
GF
Perrone
Giuseppe
G
Poeta
Maria Luana
ML
Delfino
Mario
M
Fazio
Vito Michele
VM
D000368:Aged; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism*; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D000072200:Ku Autoantigen; D008297:Male; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen