Strand asymmetry of CpG transitions as indicator of G1 phase-dependent origin of multiple tumorigenic p53 mutations in stem cells.
Strand asymmetry of CpG transitions as indicator of G1 phase-dependent origin of multiple tumorigenic p53 mutations in stem cells.
复制标题
CpG 转变的链不对称性作为干细胞中多个致瘤性 p53 突变的 G1 期依赖性起源的指标。
DOI：
10.1073/pnas.95.20.11927
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发表时间：
1998
影响因子：
11.1
通讯作者：
Rodin,AS
中科院分区：
文献类型：
--
作者：
Rodin,SN;Rodin,AS
在细胞分裂中，突变的表达是DNA链对称的。在所有源于未分裂细胞的新基因突变中，只有转录(非编码)链中的突变立即以mRNA和蛋白质的形式表达。相反，非转录(编码)链中的任何新突变都保持不表达，直到细胞进入S期并开始增殖。这一以前未被认识到的差异使我们能够检查干细胞中多个致癌突变的细胞周期依赖性来源。选择在控制G1到S相变过程中起把关作用的人p53基因进行分析。在包含在p53数据库中的所有多个突变中，我们已经详细地测试了CpG转换。CpG位点的三个特征决定了这一选择：CpG甲基化的C→T转变是mC脱氨基的直接产物，且不依赖于复制；很容易识别带有初级C→T事件的链，因为转录链上的C→T在非转录链上以G→A的形式出现；CpG转变是最频繁的(单发和多次发生)与肿瘤相关的p53突变。未分裂细胞中双非沉默CpG跃迁的起源预示着杂链(C→T，G→A)双链明显多于同源链(C→T，C→T和G→A，G→A)双链。对于P53，我们发现了这样的过剩。基于这一结果，连同本文报道的其他三项测试的结果，我们得出结论，大多数人类肿瘤的多重p53突变发生在静止的干细胞中。
In dividing cells, expression of mutations is DNA strand symmetric. Of all mutations originatingde novoin nondividing cells, only those in the transcribed (noncoding) strand are immediately expressed in mRNA and protein. In contrast, any new mutation in the nontranscribed (coding) strand remains unexpressed until the cells enter S phase and begin proliferation. This previously unrecognized difference enables us to examine the cell cycle-dependent origin of multiple tumorigenic mutations in stem cells. The humanp53gene, which acts as a gatekeeper in the control of G1to S phase transition, was chosen for the analysis. Of all multiple mutations contained in p53 databases, we have tested in detail CpG transitions. Three features of CpG sites dictate this choice: C → T transitions at methylatedmCpG are the direct product ofmC deamination and are replication-independent; it is easy to identify the strand bearing a primarymC → T event because C → T on the transcribed strand appears as G → A on the nontranscribed strand; and CpG transitions are the most frequent (as both singular and multiple occurrences) tumor-related p53 mutations. The origin of double nonsilent CpG transitions in nondividing cells predicts a significant excess of the heterostrand (C → T, G → A) doublets over the homostrand (C → T, C → T and G → A, G → A) doublets. Forp53, we found such an excess. Based on this result, along with the results of three other tests reported here, we conclude that the majority of multiple p53 mutations from human tumors occurred in quiescent stem cells.