PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage
PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage
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DOI：
10.1038/sj.onc.1205227
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发表时间：
2002-03-07
期刊：
影响因子：
8
通讯作者：
Pelicci, PG
中科院分区：
文献类型：
--
作者：
Carbone, R;Pearson, M;Pelicci, PG
PML核体（PML NB）对包括病毒感染、热休克、砷和癌基因在内的多种细胞应激反应，并且参与p53依赖的复制性衰老和凋亡的调节。最近，hMre 11/Rad 50/NBSI修复复合物，参与双链断裂（DSB）修复，被发现共定位在PML NB内，这表明这些核亚结构域在DNA修复信号通路中的作用。我们在这里报告，在正常人成纤维细胞，电离辐射（IR）后，PML NB被修改，并识别DNA断裂（ssDNA断裂和DSB）的网站。辐射后8至12小时，PML NB与hMre 11电离辐射诱导的病灶（IRIF）相关，随后与离散病灶内的p53相关。PML、hMre 11和p53共定位结构标记DSB的位点，如通过抗磷酸化组蛋白γ-H2 AX的免疫定位所鉴定的。此外，我们证明，电离辐射诱导p53与hMre 11和PML的稳定协会。这些结果表明，PML NB参与识别和/或处理DNA断裂，并可能参与招募检查点和DNA修复反应所需的蛋白质（p53和hMre 11）。
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/NBSI 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.