Toxic DNA: a model for all domains of life (360G-Wellcome-212193_Z_18_Z)

The instructions for life are encoded by DNA. As such, it is counter intuitive that certain DNA sequences can be intrinsically toxic to the cell. The problem is acute for DNA where the frequency of adenine and thymine exceeds what is normal for a given organism. Toxic effects of such "AT-rich" DNA have been reported for species as diverse as E. coli and humans. Working with bacteria, I have shown that misdirection of transcription is closely linked to the toxicity of AT-rich DNA. This happens because promoters, the DNA sequences that instigate transcription, are also AT-rich. Since promoters from all cell types have a high AT-content, I argue this may be a universal phenomenon. If true, the implications are far reaching; AT-rich DNA impacts processes as diverse as antibiotic resistance in bacteria and cancer in humans. My application probes the mechanistic details underlying the toxicity of AT-rich DNA for both prokaryotic and eukaryotic cell types. Hypothesis: The toxicity of AT-rich DNA is a consequence of spurious transcription Aim 1. Understand molecular basis Aim 2. Understand toxic mechanisms Aim 3. Understand evolutionary prevalence