Current Research Projects
Our primary experimental systems are two E. coli bacteriophages, lambda and 186. These temperate phages can replicate their genomes using alternative developmental pathways, lysis and lysogeny, and are some of the simplest organisms to make developmental decisions. Despite their relative simplicity, the phage systems combine a wide range of gene control mechanisms in complex ways and have many lessons to teach us. Bacteriophage lambda continues to be a key model system for many molecular biological processes; phage 186 is less well characterised but provides a powerful comparison with lambda, as it achieves similar outcomes using different regulatory circuits. The fundamental biochemistry shared by all living things means that the study of any organism, from phages to humans, continues to illuminate universal principles that apply to all organisms.
- 1. Traffic on DNA Dislodgement of Transcription Factors by RNA Polymerase
RNA polymerases travelling along the DNA in order to express genes often collide with proteins bound to the DNA. The outcomes of these collisions are crucial in gene regulation, yet the factors that determine the ‘winner’ – whether the DNA-bound protein blocks transcription by RNA polymerase or whether the polymerase dislodges the protein and interferes with its function – are unknown.
This project will investigate what happens when passing RNA polymerases dislodge a DNA-bound repressor or activator. Does dislodgment cause a repressed promoter to be derepressed or an activated promoter to be inhibited? Or does the dislodgement have no effect on regulation by the transcription factor? Do different transcription factors respond differently? What are the factors (e.g. RNAP frequency, DNA looping, TF concentration) that minimize or maximize the effects of dislodgement?
- 2. How does the 186 Anti-Repressor Protein Flip the Genetic Switch from Lysogeny to Lytic Development?
Prophage induction, or switching from the stable lysogenic state to the phage-producing lytic state involves removal of the master repressor in response to transient environmental signals, such as those that induce DNA damage. In phage lambda, this is achieved through proteolysis of the CI repressor. In bacteriophage 186 however, the same result is achieved by a specific protein-protein interaction. In response to DNA damage, 186 produces an anti-repressor protein, Tum, which inactivates the CI repressor. The aim of this project is to understand the mechanism of action of the anti-repressor.
- Funding Sources
Funding sources include Human Frontiers Science Program (HFSP), the Australian Research Council (ARC) and the National Health and Medical Research Council (NHMRC).
The rational design of new genetic circuits for use in synthetic biology
(Funded by ARC 2011-2013)
Quantitative analysis of the DNA loop-domain model for long range regulation of transcription
Funded by HFSP 2009-2012
‘DNA traffic’ - interactions between elongating RNA polymerases and residents of DNA
(funded by ARC 2011-2013)
View a Java based interactive model of DNA traffic
Mechanisms of propagation and containment of gene silencing (Ian Dodd)
(funded by NHMRC 2012-2014)
Flipping the switch: rational design of genetic circuits that respond to transient signals. ARC Discovery project DP150103009 (2015-2017) $241,000.
View a Java based interactive model of a nucleosome modification circuit