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*EASTBIO* Dissecting the structure and function of a highly unusual bacteriophage DNA ligase

  • Full or part time
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

BBSRC Thematic Group: Frontier Bioscience
In all forms of life, DNA ligase enzymes are essential for joining strands of DNA when new DNA is being made or when damaged DNA is being repaired. We have shown that T5-like bacteriophages (Tequintaviruses) encode a highly unusual DNA ligase that is split into two separate parts. This structural organisation - which is unprecedented in DNA ligase biology - is an evolutionarily conserved feature of all T5-like bacteriophages, implying that having a split DNA ligase is crucial for successful phage infection.

The central goals of this project are [1] to determine why the T5-like bacteriophages encode this highly unusual split DNA ligase enzyme and [2] to understand how this remarkable enzyme works at the atomic level. The fact that the ORFs encoding the N- and C-terminal portions of the enzyme are adjacent on the phage genome would allow them to be fused together simply by deleting the intervening sequence. Yet this does not occur: all sequenced T5-like phage retain the tandem split ORF configuration, suggesting that having a split ligase is essential or highly advantageous for the phage life cycle. Why? The student will address this question by developing CRISPR-Cas9 genome editing protocols to allow us to manipulate the T5 ligase ORFs and examine the consequences. One exciting possibility is that there is a connection between the split DNA ligase and a second highly distinctive feature of the T5-like phage: the presence of single-stranded nicks in the linear dsDNA packaged genomes. The student will test this hypothesis and determine the biological function of the split ligase.

In addition, the student will also work to elucidate the structural mechanism of the enzyme by solving three-dimensional structures of a split DNA ligase, without and with a DNA substrate. These atomic structures will reveal how the two portions of the enzyme come together to form a functional whole.

Taken together, the results of this work will provide comprehensive insight into the biological function, structure and enzymatic mechanism of the highly unusual split DNA ligase encoded by the T5-like bacteriophages. In addition, the development of genome editing tools for T5 will open up new avenues of investigation into T5-like phage biology, by allowing systematic analysis of gene function in a manner that is currently not possible but which will be necessary to allow us to unravel the complexities of T5-like phage infection.

Training: The student will acquire skills in microbiology, molecular biology (including CRISPR-Cas9 genome editing in bacteriophage), biochemistry and structural biology in well-equipped labs in St Andrews and Edinburgh.

Funding Notes

This project is eligible for the EASTBIO Doctoral Training Partnership: View Website

This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body.

Apply by 5.00 pm on 5 January 2020 following the instructions on how to apply at: View Website

Please also upload the EASTBO Application Form as an additional document to the University of St Andrews online Application.

Informal inquiries to the primary supervisor are very strongly encouraged.

How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

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

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