V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors
V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors
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DOI：
10.1101/gad.10.16.2038
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发表时间：
1996-08-15
影响因子：
10.5
通讯作者：
Danska, JS
中科院分区：
文献类型：
--
作者：
Guidos, CJ;Williams, CJ;Danska, JS
双链DNA断裂(DSB)触发P53介导的细胞周期停滞或凋亡通路，限制了暴露于遗传毒性药物的致癌后果，但P53介导的对正常生理事件产生的DSB的反应尚未见文献报道。由于DNA依赖蛋白激酶(DNA-PK)的突变，SCID淋巴细胞前体细胞中的V(D)J编码端“断裂”。随之而来的抗原受体有效重排的失败阻碍了淋巴的发育。在这里，我们发现SCID胸腺细胞表达高水平的P53蛋白，这归因于重组酶激活基因(RAG)依赖于V、D和J基因片段附近的DSB的产生。为了检测体内P53表达的功能重要性，我们培育了P53(-/-)SCID小鼠。P53的缺失促进了框内V(D)Jβ编码关节的产生和SCID胸腺细胞的发育进程，以及前B细胞的戏剧性积累。所有小鼠在7-12周龄时均发展为播散性Pro-B或未成熟T细胞淋巴瘤/白血病。我们提供的证据表明，p53缺乏延长了带有V(D)J编码末端断裂的SCID淋巴细胞前体细胞的存活，从而允许非整倍体细胞的积累。这些结果表明，P53介导的DNA损伤检查点有助于SCID突变的免疫缺陷特征，并限制V(D)J重组过程中产生的DSB的致癌潜力。
Double-stranded DNA breaks (DSBs) trigger p53-mediated cell cycle arrest or apoptosis pathways that limit the oncogenic consequences of exposure to genotoxic agents, but p53-mediated responses to DSB generated by normal physiologic events have not been documented. ''Broken'' V(D)J coding ends accumulate in scid lymphocyte precursors as a consequence of a mutation in DNA-dependent protein kinase (DNA-PK). The ensuing failure to rearrange efficiently antigen receptors arrests lymphoid development. Here we show that scid thymocytes express high levels of p53 protein, attributable to recombinase activating gene (RAG)-dependent generation of DSB adjacent to V, D, and J gene segments. To examine the functional importance of p53 expression in vivo, we bred p53(-/-) scid mice. The absence of p53 facilitated production of in-frame V(D)J beta coding joints and developmental progression of scid thymocytes, in addition to a dramatic accumulation of pro-B cells. All mice developed disseminated pro-B or immature T cell lymphoma/leukemia by 7-12 weeks of age. We present evidence that p53 deficiency prolongs the survival of scid lymphocyte precursors harboring broken V(D)J coding ends, allowing the accumulation of aneuploid cells. These results demonstrate that a p53-mediated DNA damage checkpoint contributes to the immune deficiency characteristic of the scid mutation and limits the oncogenic potential of DSBs generated during V(D)J recombination.