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首页> 外文期刊>Molecular and Cellular Biology >53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice
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53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice

机译：53BP1与p53协同作用，并作为小鼠单倍型不足的肿瘤抑制因子

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p53 binding protein 1 (53BP1) is a putative DNA damage sensor that accumulates at sites of double-strand breaks (DSBs) in a manner dependent on histone H2AX. Here we show that the loss of one or both copies of 53BP1 greatly accelerates lymphomagenesis in a p53-null background, suggesting that 53BP1 and p53 cooperate in tumor suppression. A subset of 53BP1?/? p53?/? lymphomas, like those in H2AX?/? p53?/? mice, were diploid and harbored clonal translocations involving antigen receptor loci, indicating misrepair of DSBs during V(D)J recombination as one cause of oncogenic transformation. Loss of a single 53BP1 allele compromised genomic stability and DSB repair, which could explain the susceptibility of 53BP1+/? mice to tumorigenesis. In addition to structural aberrations, there were high rates of chromosomal missegregation and accumulation of aneuploid cells in 53BP1?/? p53+/+ and 53BP1?/? p53?/? tumors as well as in primary 53BP1?/? splenocytes. We conclude that 53BP1 functions as a dosage-dependent caretaker that promotes genomic stability by a mechanism that preserves chromosome structure and number.
机译：p53结合蛋白1（53BP1）是一种假定的DNA损伤传感器，其以依赖组蛋白H2AX的方式累积在双链断裂（DSB）的位点。在这里，我们表明丢失一个或两个副本的53BP1大大加速了p53-null背景下的淋巴瘤的发生，这表明53BP1和p53在肿瘤抑制中协同作用。 53BP1 ？/？ p53 ？/？淋巴瘤的一个子集，就像H2AX ？/？ p53 ？/？ sup>小鼠是二倍体，具有涉及抗原受体基因座的克隆易位，表明在V（D）J重组过程中DSB修复不当是致癌性转化的原因之一。单个53BP1等位基因的缺失会损害基因组稳定性和DSB修复，这可以解释53BP1 + /？小鼠对肿瘤发生的敏感性。除结构畸变外，53BP1 ？/？ p53 + / + 和53BP1 ？/？< / sup> p53 ？/？肿瘤以及原发性53BP1 ？/？脾细胞。我们得出的结论是53BP1充当剂量依赖性看守人，可通过保留染色体结构和数目的机制来促进基因组稳定性。

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