Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita
Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita
复制标题
DOI：
10.1038/emboj.2010.83
复制
发表时间：
2010-06-02
期刊：
影响因子：
11.4
通讯作者：
Ruggero, Davide
中科院分区：
文献类型：
--
作者：
Bellodi, Cristian;Kopmar, Noam;Ruggero, Davide
核糖体生物发生和功能缺陷存在于越来越多的与癌症易感性相关的人类综合征中。一个例子是x连锁先天性角化不良症（X-DC），其中编码修饰核糖体RNA的酶的DKC1基因被发现发生突变。核糖体功能障碍如何导致癌症仍然知之甚少。一个关键的细胞反应，抵消细胞转化是癌基因诱导的衰老（OIS）。在这里，我们发现在OIS期间，帽和内部核糖体进入位点（IRES）依赖的翻译之间发生切换。在这个转换过程中，位于p53 5'非翻译区的IRES元件参与并促进p53的翻译。我们进一步表明，在DKC1 m细胞中，p53 ires依赖的翻译在体外OIS和体内DNA损伤期间受损。p53翻译中的这种缺陷扰乱了细胞对抗致癌损伤的反应。我们将这些发现扩展到X-DC人类患者细胞中，观察到p53 ires依赖翻译的类似损伤。重要的是，重新引入野生型DKC1可以恢复这些细胞中的p53表达。这些结果为与核糖体功能障碍相关的人类综合征的癌症易感性基础提供了见解。EMBO杂志（2010）29,1865-1876。doi: 10.1038 / emboj.2010.83;2010年5月7日在线发布
Defects in ribosome biogenesis and function are present in a growing list of human syndromes associated with cancer susceptibility. One example is X-linked dyskeratosis congenita (X-DC) in which the DKC1 gene, encoding for an enzyme that modifies ribosomal RNA, is found to be mutated. How ribosome dysfunction leads to cancer remains poorly understood. A critical cellular response that counteracts cellular transformation is oncogene-induced senescence (OIS). Here, we show that during OIS, a switch between cap-and internal ribosome entry site (IRES)-dependent translation occurs. During this switch, an IRES element positioned in the 5'untranslated region of p53 is engaged and facilitates p53 translation. We further show that in DKC1 m cells, p53 IRES-dependent translation is impaired during OIS ex vivo and on DNA damage in vivo. This defect in p53 translation perturbs the cellular response that counteracts oncogenic insult. We extend these findings to X-DC human patient cells in which similar impairments in p53 IRES-dependent translation are observed. Importantly, re-introduction of wild-type DKC1 restores p53 expression in these cells. These results provide insight into the basis for cancer susceptibility in human syndromes associated with ribosome dysfunction. The EMBO Journal (2010) 29, 1865-1876. doi:10.1038/emboj.2010.83; Published online 7 May 2010