期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：20
页码：11927-11932
DOI：10.1073/pnas.95.20.11927
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：In dividing cells, expression of mutations is DNA strand symmetric. Of all mutations originating de novo in 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 human p53 gene, which acts as a gatekeeper in the control of G1 to 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 methylated mCpG are the direct product of mC deamination and are replication-independent; it is easy to identify the strand bearing a primary mC [->] 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. For p53, 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.
