Spontaneous multiple mutations show both proximal spacing consistent with chronocoordinate events and alterations with p53-deficiency
Spontaneous multiple mutations show both proximal spacing consistent with chronocoordinate events and alterations with p53-deficiency
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DOI：
10.1016/j.mrfmmm.2004.05.005
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发表时间：
2004-10-04
影响因子：
2.3
通讯作者：
Sommer, SS
中科院分区：
文献类型：
--
作者：
Hill, KA;Wang, JC;Sommer, SS
对正常细胞和肿瘤细胞中自发的多种突变进行分析，可能会对导致多种突变的机制假说形成限制，并为突变体表型提供深入了解。在先前的一项研究中，“大蓝”（Big Blue®）小鼠中的自发双突变体出现的频率远远高于随机预期，并且其突变模式与单突变所观察到的相似[《突变研究》452 (2000) 219]。双突变体中突变之间的间距通常比随机预期更紧密，并且突变间距的分布符合指数分布，尽管存在较大的离散度。我们现在对另外2658个突变体进行分析，并证实双突变体相对于随机预期有显著增加。在新的数据以及综合数据中，我们将自发双突变体和多突变体（多个突变体）的间距、频率和模式作为年龄、组织类型、p53缺失以及肿瘤形成的函数进行研究。新的数据和综合数据证实，双突变体中突变之间的间距分布是非随机的，突变间距比随机预期更紧密（P < 0.0005；综合数据），这与时间上协调（时间协同）的事件是一致的。指数分布对该分布有很好的拟合（R² = 0.98），并且估计半数双突变体的突变间距为120个核苷酸或更小（“突变间距的半衰期”）。我们有几个新的发现：（i）单突变体和双突变体的频率总体上都随年龄增长而相似地增加；（ii）双突变体在雄性生殖系中的频率可能较低，这与雄性生殖系中普遍降低的突变频率是一致的；（iii）在p53缺失小鼠（李 - 弗劳梅尼癌症综合征模型；P = 0.005）的体细胞组织中双突变体频率升高；（iv）p53缺失小鼠肿瘤中的双突变体和单突变体具有不同的突变模式（P = 0.007）。这些观察结果与由于短暂的易错状态导致的自发双突变体和多突变体的时间协同发生是一致的，并且不表明最近发现的易错Y家族聚合酶起主要作用。p53缺失小鼠中双突变体的增加可能会增加癌症风险。(C) 2004 Elsevier B.V. 保留所有权利。
Analysis of spontaneous multiple mutations in normal and tumor cells may constrain hypotheses about the mechanisms responsible for multiple mutations and provide insight into the mutator phenotype. In a previous study, spontaneous doublets in Big Blue(R) mice were dramatically more frequent than expected by chance and exhibited a mutation pattern similar to that observed for single mutations [Mutat. Res. 452 (2000) 219]. The spacing between mutations in doublets was generally closer than expected by chance and the distribution of mutation spacing fit an exponential, albeit with substantial scatter. We now analyze 2658 additional mutants and confirm that doublets are enhanced dramatically relative to chance expectation. The spacing, frequency and pattern of spontaneous doublets and multiplets (domuplets) are examined as a function of age, tissue type, p53-deficiency and neoplasia in the new and combined data. The new and combined data confirm that the distribution of the spacing between mutations in doublets is non-random with the mutations more closely spaced than expected by chance (P < 0.0005; combined data), consistent with temporally coordinate (chronocoordinate) events. An exponential provides an excellent fit to the distribution (R-2 = 0.98) and estimates that half of doublets have mutations separated by 120 nucleotides or less (the "half-Life of mutation spacing"). We make several novel observations: (i) singlets and doublets show similar overall increases in frequency with age (ii) doublet frequency may be lower in the male germline, consistent with the generally reduced mutation frequency in the male germline (iii) doublet frequencies are elevated in somatic tissues of p53-deficient mice (Li-Fraumini cancer syndrome model; P = 0.005) and (iv) doublets and singlets in tumors from p53-deficient mice have a different mutation pattern (P = 0.007). The observations are consistent with chronocoordinate occurrence of spontaneous doublets and multiplets due to a transient error-prone condition and do not suggest a major role for the recently discovered Y family of error-prone polymerases. The enhancement of doublets in p53-deficient mice may contribute to cancer risk. (C) 2004 Elsevier B.V. All rights reserved.