Dihydrofolate reductase interactome: an unrecognised network that can control DNA synthesis and cell replication (360G-Wellcome-202056_Z_16_Z)

We aim to characterise and map the interactome of dihydrofolate reductase (DHFR), a well-validated anticancer drug target. DHFR is an enzyme that catalyses a key reaction in the biosynthesis of DNA building blocks. Although therapeutics targeting DHFR are available for cancer treatment, resistance against them is frequently found. To combat against this issue, it is essential to fully characterise DHFR, from its catalytic behaviours to regulatory network, as this information will find uses for future drug development. DHFR binds to a wide variety of biomolecules other its substrates, including its parental mRNA and enzymes responsible for post-translational modifications (PTMs). We believe that it is crucial to investigate these non-substrate interactions, as their functional roles have not identified. We hypothesise that DHFR is embedded in a molecular network of interactions that are responsible for controlling the activity of DHFR. Based on the applicant’s expert enzymology knowledge of DHFR catalysis, we set 3 objectives to study the DHFR interactome: Characterising the effect of PTMs on DHFR catalysis; Isolating the effect of mRNA binding; and Mapping the interactome of DHFR. This work will advance our knowledge of DHFR. Lastly, publications and data generated here will also form a strong basis for grant applications.