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

<p>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.&nbsp;Toxic effects of such &quot;AT-rich&quot; DNA have been reported for species as diverse as <em>E. coli </em>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.&nbsp;</p> <p>&nbsp;</p> <p><strong>Hypothesis: The toxicity of AT-rich DNA is a consequence of spurious transcription</strong></p> <p>&nbsp;</p> <p>Aim 1. Understand <strong>molecular basis</strong></p> <p>Aim 2. Understand <strong>toxic mechanisms</strong></p> <p>Aim 3. Understand <strong>evolutionary prevalence</strong></p> <p>&nbsp;</p>

£1,138,415

17 Jul 2018

Grant details
Amount Awarded 1138415
Applicant Surname Grainger
Approval Committee Science Interview Panel
Award Date 2018-07-17T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Investigator Award in Science
Internal ID 212193/Z/18/Z
Lead Applicant Prof David Grainger
Planned Dates: End Date 2024-02-01T00:00:00+00:00
Planned Dates: Start Date 2019-02-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region West Midlands
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