title: Differential modulation of Ku70/80 DNA-binding activity in a patient with multiple basal cell carcinomas.
abstract: 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.
authors.affiliation: Laboratory for Molecular Medicine and Biotechnology, Interdisciplinary Center for Biomedical Research, Università Campus Bio-Medico, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mazzarelli
authors.forename: Carla
authors.initials: C
authors.lastname: Rabitti
authors.forename: Paola
authors.initials: P
authors.lastname: Parrella
authors.forename: Davide
authors.initials: D
authors.lastname: Seripa
authors.forename: Paolo
authors.initials: P
authors.lastname: Persichetti
authors.forename: Giovanni Francesco
authors.initials: GF
authors.lastname: Marangi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perrone
authors.forename: Maria Luana
authors.initials: ML
authors.lastname: Poeta
authors.forename: Mario
authors.initials: M
authors.lastname: Delfino
authors.forename: Vito Michele
authors.initials: VM
authors.lastname: Fazio
mesh_terms: 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
chemical_list: 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