Figure 1.

Expression asymmetry of DNA strands in nondividing cells is illustrated by CpG transitions in p53 hotspot codons 248 and 273 during p53-mediated G₁ arrest. (A) Shown is the mutant p53⁻ cell with preexisting CpG → TpG in codon 248. Because of DNA replication, the original C⋅G base pair was substituted for T⋅A before the checkpoint in G₁. The cell transcribes the mutant p53 mRNA (C → U), which is in turn translated into an altered protein (Arg248 → Trp). As a result, the cell escapes G₁ arrest and is selected for proliferation. This preexisting single CpG transition is a tumor driver. (B) Shown is the wild-type p53⁺ cell arrested in G₁ phase. The first C → T transition originates de novo in codon 248 on the coding nontranscribed strand (NTS). To be expressed, it has to wait for another, necessarily nonsilent, mutation on the transcribed strand (TS), which would release the cell from the G₁ arrest. This second mutation is shown as C → T in codon 273, on the transcribed strand. It appears as G → A in mRNA and is translated into His instead of Arg in the p53 protein. As a result, the cell enters S phase, then undergoes cell division and proliferation. The corresponding clone appears in the tumor as a p53 doublet. The first mutation is a hitchhiker, and the second mutation is a tumor driver.