Cancer predisposition and hematopoietic failure in Rad50S/S mice
Cancer predisposition and hematopoietic failure in Rad50S/S mice
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DOI：
10.1101/gad.1007902
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发表时间：
2002-09-01
影响因子：
10.5
通讯作者：
Petrini, JHJ
中科院分区：
文献类型：
--
作者：
Bender, CF;Sikes, ML;Petrini, JHJ
Mre11、Rad50和Nbs1在一种蛋白质复合体中发挥作用，该复合体是染色体断裂代谢的中心。每一种的零突变体都是不可行的。我们在这里证明了低形RAD50突变小鼠(RAD50(S/S)小鼠)表现出生长缺陷和癌症易感性。RAD50(S/S)小鼠死于进行性造血干细胞衰竭所致的骨髓完全耗竭。生精细胞中也出现了类似的损耗。在这两种情况下，P53缺乏显著减轻了磨损，而RAD50缩短了P53(-/-)和P53(+/-)动物的肿瘤潜伏期(S/S)。在培养的RAD50(S/S)细胞，以及在RAD50(S/S)和P53(-/-)RAD50(S/S)淋巴瘤中，都有明显的遗传毒性应激和染色体重排指标，提示RAD50(S/S)的表型与染色体不稳定有关。这些结果与Mre11复合体先前建立的双链断裂修复和细胞周期检查点调节功能的明显缺陷无关。这些数据表明，即使是微小的Mre11复合体功能的干扰也会导致严重的遗传毒性应激，并且该复合体对增殖组织的动态平衡至关重要。
Mre11, Rad50, and Nbs1 function in a protein complex that is central to the metabolism of chromosome breaks. Null mutants of each are inviable. We demonstrate here that hypomorphic Rad50 mutant mice (Rad50(S/S) mice) exhibited growth defects and cancer predisposition. Rad50(S/S) mice died with complete bone marrow depletion as a result of progressive hematopoietic stem cell failure. Similar attrition occurred in spermatogenic cells. In both contexts, attrition was substantially mitigated by p53 deficiency, whereas the tumor latency of p53(-/-) and p53(+/-) animals was reduced by Rad50(S/S). Indices of genotoxic stress and chromosomal rearrangements were evident in Rad50(S/S) cultured cells, as well as in Rad50(S/S) and p53(-/-) Rad50(S/S) lymphomas, suggesting that the Rad50(S/S) phenotype was attributable to chromosomal instability. These outcomes were not associated with overt defects in the Mre11 complex's previously established double strand break repair and cell cycle checkpoint regulation functions. The data indicate that even subtle perturbation of Mre11 complex functions results in severe genotoxic stress, and that the complex is critically important for homeostasis of proliferative tissues.