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Why do some DNA sequences poison cells?

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Life on our planet is permitted by an ancient set of instructions encoded by DNA. Consequently, the observation that a cell can be poisoned by its own DNA is completely counterintuitive. The phenomenon results from the intrinsic toxicity of certain DNA sequences. Such sequences, initially conspicuous as being “unclonable”, are frequently rich in adenine (A) and thymine (T) bases (1). The toxicity of this “AT-rich” DNA has been documented in diverse cell types but, despite having implications for all DNA based life, a molecular explanation is lacking. The significance of toxic DNA is best understood for bacteria, where “silencing” proteins bind AT-rich sequence to nullify its effects (1). My lab’s recent focus has been to understand how these “silencing” proteins function. Our work has targeted the bacterial H-NS protein (2,3). Contrary to expectations, we have shown that a major role of H NS is to prevent spurious transcription initiating within the coding sequences of AT-rich genes (2,3,4). Thus, we propose that AT-rich DNA is toxic because it promotes spurious intragenic RNA synthesis. This is a simple consequence of RNA polymerase having a clear preference for binding AT-rich DNA. Intriguingly, this characteristic of RNA polymerase is conserved throughout life. You project will aim to understand molecular mechanisms of DNA toxicity and its evolutionary conservation.

For more information on Dr Grainger’s lab and research please visit: http://graingerlab.com/

Funding Notes

Project can be funded by the MIBTP-BBSRC training programme (UK and EU students) or a Darwin Trust scholarship (Worldwide). Please state in application which scheme you wish to be considered for. For MIBTP-BBSRC, you will need to fill in a University of Birmingham application AND the short notification form on the University of Warwick MIBTP portal (MIBTP is a doctoral training partnership between Warwick, Birmingham and Leicester).

Further details on the BBSRC MIBTP scheme are here: View Website
Deadline: 6 January, 2019
Number of Studentships available: 30
Stipend: RCUK standard rate (plus travel allowance and laptop).

To check eligibility visit: View Website

References

1. Dorman, CJ. (2007) H-NS, the genome sentinel. Nat. Rev. Microbiol. 5: 157-161.
2. Wade JT, Grainger DC. (2014) Pervasive transcription: illuminating the dark matter of bacterial transcriptomes. Nat. Rev. Microbiol. 12:647-53.
3. Singh SS, Singh N, Bonocora RP, Fitzgerald DM, Wade JT, Grainger DC. (2014) Widespread suppression of intragenic transcription initiation by H-NS. Genes Dev. 28:214-9.
4. Lamberte LE, Baniulyte G, Singh SS, Stringer AM, Bonocora RP, Stracy M, Kapanidis AN, Wade JT, Grainger DC. (2017) Horizontally acquired AT-rich genes in Escherichia coli cause toxicity by sequestering RNA polymerase. Nat Microbiol. 2:16249.

How good is research at University of Birmingham in Biological Sciences?

FTE Category A staff submitted: 42.80

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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