Highly activated transcription is associated with eukaryotic genome
instability, resulting in increased rates of
mitotic recombination and mutagenesis. The association between high transcription and genome stability is probably due to a variety of factors including an enhanced accumulation of
DNA damage, transcription-associated
supercoiling, collision between
replication forks and the transcription machinery, and the persistence of RNA-DNA hybrids. In the case of transcription-associated mutagenesis, we previously showed that there is a direct proportionality between the level of transcription and the
mutation rate in the
yeast Saccharomyces cerevisiae, and that the molecular nature of the
mutations is affected by highly activated transcription. Here we show that the accumulation of apurinic/
apyrimidinic sites is greatly enhanced in highly transcribed
yeast DNA. We further demonstrate that most apurinic/
apyrimidinic sites in highly transcribed
DNA are
derived from the removal of
uracil, the presence of which is linked to direct incorporation of dUTP in place of dTTP. These results show an unexpected relationship between transcription and the fidelity of
DNA synthesis, and raise intriguing cell biological issues with regard to
nucleotide pool compartmentalization.
