Petrini John H J, Theunissen Jan-Willem F
Molecular Biology Program, Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA.
Cell Cycle. 2004 May;3(5):541-2. doi: 10.4161/cc.3.5.835. Epub 2004 May 8.
Hypomorphic mutants affecting the Mre11 complex components Mre11 (Mre11(ATLD1/ATLD1)) and Nbs1 (Nbs1(DeltaB/DeltaB)) have been established in the mouse. These mutations recapitulate those inherited in human chromosome fragility syndromes, the ataxia-telangiectasia like disorder and Nijmegen breakage syndrome. At the cellular level, the human and murine mutants exhibit defects in the intra S and G2/M checkpoints and marked chromosome instability. Whereas these outcomes are associated with predisposition to malignancy in humans, similar predisposition was not observed in either Mre11(ATLD1/ATLD1) or Nbs1(DeltaB/DeltaB) mice. These data demonstrate that chromosome breakage per se is insufficient to significantly enhance the initiation of tumorigenesis. However, these mutations greatly enhanced the risk of malignancy in p53+/- mice. We propose that proper metabolism of chromosome breaks arising during DNA replication is uniquely important for suppressing loss of heterozygosity and thus the penetrance of recessive oncogenic lesions.
在小鼠中已建立了影响Mre11复合物组分Mre11（Mre11(ATLD1/ATLD1)）和Nbs1（Nbs1(DeltaB/DeltaB)）的亚效突变体。这些突变重现了人类染色体脆性综合征、共济失调毛细血管扩张样障碍和尼曼匹克氏断裂综合征中所遗传的突变。在细胞水平上，人类和小鼠突变体在S期内和G2/M期检查点存在缺陷，并表现出明显的染色体不稳定。虽然这些结果与人类的恶性肿瘤易感性相关，但在Mre11(ATLD1/ATLD1)或Nbs1(DeltaB/DeltaB)小鼠中均未观察到类似的易感性。这些数据表明，染色体断裂本身不足以显著增强肿瘤发生的起始。然而，这些突变极大地增加了p53+/-小鼠的恶性肿瘤风险。我们提出，DNA复制过程中产生的染色体断裂的适当代谢对于抑制杂合性缺失从而抑制隐性致癌病变的外显率具有独特的重要性。
