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Understanding the biological function of a highly unusual bacteriophage DNA ligase

  • Full or part time
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

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 (1). 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 goal of this project is to determine why the T5-like bacteriophages encode this highly unusual split DNA ligase enzyme. 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 (2) 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 phage genomes. The student will test this hypothesis and determine the biological function of splitting the ligase. 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.
The student will acquire skills in molecular microbiology (including CRISPR-Cas9 genome editing in bacteriophage), biochemistry and bioinformatics.

Funding Notes

Eligibility requirements: A good BSc (Hons) degree (2:1 or above) or equivalent in molecular biology, microbiology, biochemistry or a related subject is essential. A research Masters degree in an area of biology related to the project is desirable.
Funding source: School of Biology.
Duration: 3.5 years fees and stipend.

References

1. Wang, J. et al. (2005) Complete genome sequence of bacteriophage T5. Virology 332(1):45-65.
2. Hatoum-Aslan A (2018) Phage genetic engineering using CRISPR-Cas systems. Viruses 10(6). pii: E335. doi: 10.3390/v10060335.

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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