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What is the role of uracil in DNA?

Primary Supervisor: Professor Yin Chen, School of Life Sciences

Secondary supervisor: Professor David Scanlan & Dr Richard Puxty, School of Life Sciences

PhD project title: What is the role of uracil in DNA?

University of Registration: University of Warwick

Project outline:

Although textbooks tell us that DNA comprises just four bases (T base pairing with A, and G base pairing with C) and that uracil is only found in RNA, we and others have recently demonstrated that uracil can be found in the DNA of several bacteriophages, where uracil (instead of T) forms base pairing with A (1-4). Bacteriophages, viruses that specifically infect bacteria, are the most abundant biological entities on the planet. They are often found at concentrations of up to 10 million per milliliter of seawater, with an estimate of 4 × 1030 viruses in the oceans (5). Bacteriophages are also extremely abundant in the human gut with an estimate of ~1012 viruses residing in this environment where they not only shape the diversity of gut microbial communities but also complicate the development of various human diseases. More generally bacteriophages play a crucial role in the re-allocation of nutrients via cell lysis, drive marine species diversification and evolution through a phage-host arms race and regulate biogeochemical cycles by shunting nutrients into the microbial food-web (5).

In our recent work, we have obtained two bacteriophages (DSS3_PM1 and DSS3_VP1) which contain full substitution of T by uracil in their genomes (1). Given that uracil-containing DNA bacteriophages appear difficult to isolate and have only been reported previously in four independent studies over the past 60 years, our uracil-containing DNA bacteriophages are therefore precious material to tackle the fundamental question – what is the role of uracil in DNA? We aim to determine how uracil DNA is made in these bacteriophages, as well as the host and phage factors involved in the synthesis of uracil. Furthermore, we will determine the biological function of uracil in these bacteriophages through comparative proteomics/transcriptomics. This project will transform our understanding of the role of uracil, a noncanonical DNA base, in biology.

References:

  1. Rihtman B, Puxty RJ, Hapeshi A, Lee Y-J, Zhan Y, Michniewski S, Waterfield NR, Chen F, Weigele P, Millard AD, Scanlan DJ, Chen Y (2021) A new family of globally distributed lytic roseophage, the Naomiviridae, has unusual thymidine to deoxyuridine substitution. Current Biology, https://doi.org/10.1016/j.cub.2021.05.014.
  2. Takahashi I, Marmur J. (1963) Replacement of thymidylic acid by deoxyuridylic acid in the deoxyribonucleic acid of a transducing phage for Bacillus subtilis. 197:794–795
  3. Kiljunen, S.; Hakala, K.; Pinta, E.; Huttunen, S.; Pluta, P.; Gador, A.; Lonnberg, H.; Skurnik, M. (2005) Yersiniophage phiR1-37 is a tailed bacteriophage having a 270 kb DNA genome with thymidine replaced by deoxyuridine. Microbiology 151: 4093–4102.
  4. Uchiyama, J.; Takemura-Uchiyama, I.; Sakaguchi, Y.; Gamoh, K.; Kato, S.; Daibata, M.; Ujihara, T.; Misawa, N.; Matsuzaki, S. (2014) Intragenus generalized transduction in Staphylococcus by a novel giant phage. ISME J. 8, 1949–1952.
  5. Suttle CA (2005). Viruses in the sea. Nature. 437:356–61.

BBSRC Strategic Research Priority: Understanding the rules of life: Microbiology

Techniques that will be undertaken during the project:

  • Cutting edge ‘omics tool sets and associated bioinformatics, including lipidomics, and proteomics
  • Molecular genetics of microbiology and phage biology
  • Analytical skills including HPLC-MS

Contact: Professor Yin Chen, University of Warwick