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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice
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XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice

机译：XRCC4抑制p53缺陷小鼠复发性易位的髓母细胞瘤

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Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.
机译：小鼠种系中XRCC4非同源末端连接因子的失活导致胚胎致死性，与新产生的有丝分裂后神经元的凋亡相关。我们现在显示，表达巢蛋白的神经元祖细胞中XRCC4的条件失活，尽管在WT背景下不导致明显的表型，但在p53缺乏的背景下导致神经元分化的髓母细胞瘤（MBs）的早期发作。大量XRCC4 / p53缺失的MB具有高水平的N-myc基因扩增，通常在复杂易位或N-myc所在的12号染色体发生其他移位的情况下在染色体内进行，或者在两分钟内在染色体外进行。此外，大多数XRCC4 / p53缺陷型MB具有13号染色体的克隆易位，而13号染色体通常与6号染色体为伴。在所有测试的XRCC4 / p53缺陷型MB中，在易位或间质缺失的背景下，删除了位于13号染色体上的修补基因（Ptc）的一个副本。此外，Cyclin D2是第6号染色体基因，在一部分肿瘤中被扩增。值得注意的是，还已经在人MB中观察到Myc家族或Cyclin D2基因的扩增和Ptc的缺失。因此，我们得出的结论是，在小鼠的神经元细胞中，非同源末端连接途径在抑制基因组不稳定性方面起着关键作用，在p53缺乏的背景下，该基因组不稳定性通常会导致具有复发性染色体改变的MB的发生。

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