O ⁶ -methylguanine–induced transcriptional mutagenesis reduces p53 tumor-suppressor function

Significance The impact of DNA lesions on replication and mutagenesis is of high relevance for human health; however, the role of lesion-induced transcriptional mutagenesis (TM) in disease development is unknown. Here, the impact of O 6 -methylguanine–induced TM on p53 function as a tumor suppressor was investigated in human cells. Results showed that TM in 15% of the transcripts resulted in a reduced ability of p53 protein to transactivate genes that regulate cell-cycle arrest and induction of apoptosis. This resulted in the loss of functional cell-cycle checkpoints and in impaired activation of apoptosis, both canonical p53 tumor-suppressor functions. This work provides evidence that TM can induce phenotypic changes in mammalian cells that have important implications for its role in tumorigenesis.