Transcriptional mutagenesis: causes and involvement in tumour development

Abstract

The majority of human cells do not multiply continuously but are quiescent or slow-replicating and devote a large part of their energy to transcription. When DNA damage in the transcribed strand of an active gene is bypassed by a RNA polymerase, they can miscode at the damaged site and produce mutant transcripts. This process is known as transcriptional mutagenesis and, as discussed in this Perspective, could lead to the production of mutant proteins and might therefore be important in tumour development.

Figure 1. DNA replication-independent production of erroneous proteins

Under normal conditions (top left), transcription in the nucleus (pale blue background) produces error-free mRNAs that are translated by ribosomes (double blue ovals) to normal proteins (green ovals) in the cytoplasm. In some cases (top right), lapses in RNA polymerase fidelity (orange ovals) can generate aberrant transcripts (red dot) that are translated into erroneous proteins (red jagged ovals). This random low frequency production of erroneous proteins can also be due to translational errors or to lapses in translation fidelity. When exposed to a genotoxic agent (red thunderbolt) (bottom left), RNA molecules in a cell may contain lesions (red triangles) that could induce the production of erroneous proteins during translation because of their potentially altered specificities of codon/anticodon pairing during tRNA selection. DNA is the other target for genotoxic stress (bottom right). RNA polymerase can bypass numerous unrepaired damaged nucleotides on the transcribed strand of a gene (red triangle) that can result in misincorporation events in the transcript sequence (red dots) as long as the DNA damage is not removed by one of the cellular DNA repair pathways (green arrow). Transcriptional mutagenesis results in the production of a primarily homogenous mutant transcript population that, in turn, lead to the production of high levels of erroneous proteins, all possessing the same mutant sequence, that could alter the phenotype of the cell.

Figure 2. Potential role of transcriptional mutagenesis in tumor development

Following genotoxic stress (red thunderbolt), a DNA lesion (red triangle) can appear on the transcribed strand of a gene resulting in the production of high levels of erroneous protein via transcriptional mutagenesis as shown in Figure 1. The resulting mutant proteins (red jagged ovals) may have the ability to alter the phenotype of the cell in such a way as to confer a growth advantage leading to initiation of DNA replication. If left unrepaired, the DNA lesion will subsequently be encountered by the replication machinery (blue ovals, DNA synthesizing lagging and leading strands) and will likely cause similar miscoding during DNA synthesis resulting in the fixation of the mutation into the genome of one progeny cell (bottom right). Subsequent rounds of replication in this progeny will lead to a dividing cell population harboring the mutation that conferred the growth advantage and thus could lead to tumor development. Double blue ovals, ribosomes; orange ovals, RNA polymerase ; red dots, misincorporated nucleotides; green ovals, normal proteins.