Transcriptional mutagenesis and its potential roles in the etiology of cancer and bacterial antibiotic resistance

Abstract

Most cells do not undergo continuous cell division and DNA replication, yet they can still acquire novel RNA mutations that can result in the production of mutant proteins and induce a phenotypic change. All cells are frequently subjected to genotoxic insults that give rise to damaged nucleotides which, similarly to DNA replication, can undergo base mispairing during transcription. This mutagenic lesion bypass by RNA polymerase, transcriptional mutagenesis (TM), has been studied in a variety of systems and organisms, and may be involved in diverse pathogenic processes, such as tumorigenesis and the acquisition of bacterial antibiotic resistance. Tumor cells and bacteria within the human body are subject to especially high levels of oxidative stress, which can damage DNA and consequently drive TM. Mutagenesis at the level of transcription may allow cells to escape growth arrest and undergo replication that could permanently establish mutations in DNA in a process called retromutagenesis (RM). Here, we review the broad range of DNA damages which may result in TM including a variety of non-bulky lesions and some bulky lesions, which recent studies indicate may not completely block transcription, and emerging evidence supporting the RM concept in the context of tumorigenesis and antibiotic resistance.

Figure 1

Potential phenotypic consequences of DNA damage during transcription. A: Some BER substrates, such as thymine glycol (Tg) (Charlet-Berguerand et al., 2006), can be bypassed with only low levels of TM, unlikely to induce a phenotypic change. B: Some non-bulky BER substrates, such as 8-oxoG, can be bypassed and result in significant levels of TM. If the TM event drives a transcriptional gain-of-function mutation and aberrant activation of a proliferation-promoting oncogene, it may initiate tumorigenesis. In the case of bacteria, if the transcriptional mutation is such that it confers antibiotic resistance, it may allow the cells to evade cell death or cytostasis and give rise to a population of antibiotic-resistant bacteria. C: Bulky lesions that partially stall RNAP but are mutagenic may result in reduced expression of a tumor suppressor and low levels of mutant transcripts, and may allow cells to evade growth-suppressive conditions or apoptosis. Bypass of such lesions in bacteria may allow cells to acquire mutations of antibiotic target proteins, which allow them to survive antibiotic selection.