title: PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage.
abstract: PML nuclear bodies (PML NBs) respond to many cellular stresses including viral infection, heat shock, arsenic and oncogenes and have been implicated in the regulation of p53-dependent replicative senescence and apoptosis. Recently, the hMre11/Rad50/NBS1 repair complex, involved in Double Strand Breaks (DSBs) repair, was found to colocalize within PML NBs, suggesting a role for these nuclear sub-domains in the DNA repair signalling pathway. We report here that in normal human fibroblasts, after ionizing radiation (IR), the PML NBs are modified and recognize sites of DNA breaks (ssDNA breaks and DSBs). Eight to 12 h after radiation PML NBs associate with hMre11 Ionizing Radiation-Induced Foci (IRIF), and subsequently with p53 within discrete foci. The PML, hMre11 and p53 colocalizing structures mark sites of DSBs as identified by immunolocalization with anti phosphorylated histone gamma-H2AX. Furthermore, we demonstrate that ionizing radiation induces the stable association of p53 with hMre11 and PML. These results suggest that the PML NBs are involved in the recognition and/or processing of DNA breaks and possibly in the recruitment of proteins (p53 and hMre11) required for both checkpoint and DNA-repair responses.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Carbone
authors.forename: Mark
authors.initials: M
authors.lastname: Pearson
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D002478:Cells, Cultured; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000032:analysis*; D006801:Humans; D000076228:MRE11 Homologue Protein; D009363:Neoplasm Proteins / Q000032:analysis / Q000528:radiation effects*; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000032:analysis / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D025521:Tumor Suppressor Proteins; D014965:X-Rays
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D004247:DNA; D000076228:MRE11 Homologue Protein