Rodin S N, Rodin A S, Juhasz A, Holmquist G P
Biology Department, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
Mutat Res. 2002 Dec 29;510(1-2):153-68. doi: 10.1016/s0027-5107(02)00260-9.
The database of tumor-associated p53 base substitutions includes about 5% of tumors with two or more base substitutions. These multiplet base substitutions in one tumor are evidence for hyper-mutagenesis. Our retrospective analysis of this database indicates that most multiplets arise from a single transient hyper-mutagenic event in one cell that subsequently proliferated into a clonal tumor. The hyper-mutagenesis, 1.8 x 10(-4) substitutions per base pair, is detected as multiple mutations in p53 genes of tumors. It requires one strongly tumorigenic p53 substitution, usually missense, called the driver mutation. The occurrence frequencies of ancillary base substitutions, those that hitch-hike along with the driver mutation, are independent of their amino acid coding properties. In this respect, they act like neutral mutations. In support of this neutrality, we find that the frequency distribution of hitch-hiking CpG transitions along the p53 exons, their mutational spectrum, approximates the spontaneous pre-selection mutational spectrum of most human tissues and is correlated with the mutational spectrum of p53 pseudogenes in mammalian germ cells. The driver substitutions of multiplets predominantly originate along the transcribed strand while the ancillary substitutions tend to originate along the non-transcribed strand. This data is consistent with a model of time-dependent mutagenesis in non-dividing stem cells for generating multiple strand-asymmetric p53 mutations in tumors. By transcriptional bypass of DNA lesions with concomitant misincorporation, transcriptional mutagenesis generates a transient mutant p53 mRNA. The associated mutant p53 protein could allow the host cell a growth advantage, release from G1-arrest. Then, during subsequent DNA replication and misreading of the same lesion, the damaged base along the transcribed DNA strand would serve as the origin of the p53 base substitution that drives the hyper-mutagenic event leading to tumors with multiple p53 mutations.
肿瘤相关p53碱基替换数据库包含约5%存在两个或更多碱基替换的肿瘤。一个肿瘤中出现的这些多重碱基替换是高突变的证据。我们对该数据库的回顾性分析表明，大多数多重替换源于一个细胞中单个短暂的高突变事件，该细胞随后增殖形成克隆性肿瘤。高突变率为每碱基对1.8×10⁻⁴个替换，在肿瘤的p53基因中表现为多个突变。它需要一个强烈致瘤的p53替换，通常为错义突变，称为驱动突变。伴随驱动突变出现的辅助碱基替换的发生频率与其氨基酸编码特性无关。在这方面，它们的行为类似于中性突变。为支持这种中性，我们发现伴随p53外显子的搭便车CpG转换的频率分布、它们的突变谱，近似于大多数人类组织的自发预选突变谱，并且与哺乳动物生殖细胞中p53假基因的突变谱相关。多重替换的驱动替换主要沿转录链产生，而辅助替换倾向于沿非转录链产生。该数据与非分裂干细胞中随时间变化的诱变模型一致，该模型用于在肿瘤中产生多个链不对称的p53突变。通过转录绕过DNA损伤并伴随错误掺入，转录诱变产生一个短暂的突变p53 mRNA。相关的突变p53蛋白可使宿主细胞获得生长优势，从G1期阻滞中释放。然后，在随后的DNA复制和对同一损伤的错读过程中，转录DNA链上受损的碱基将作为p53碱基替换的起源，驱动导致具有多个p53突变的肿瘤的高突变事件。
