Our research program aims to elucidate the molecular function of DNA modifications in normal cells and cancer. We employ biochemistry and in vivo approaches to investigate roles of DNA modifications in transcription, heritability, mutability and nuclear organisation. Together with advancing knowledge of the basic biology of DNA, we delineate defects in cancer and aim to target them for the therapy.
Until recently, methylation of cytosine (5-methylcytosine, 5mC) was the only recognized DNA modification present in mammalian DNA. We and others have demonstrated the existence of 5-hydroxymethylcytosine (5hmC), which is a product of TET family of oxygenases acting on methylated cytosine. In cycling cells, 5hmC is a demethylation intermediate, but it is found as a long-lived base in post-mitotic cells, where its function is less well understood.
An example of our recent work is an investigation of the hypothesis that stable 5hmC may have an impact on the mutability of DNA, since 5mC is known to relate to increased C-to-T transitions. By employing computational analysis relating 5hmC localisation in normal human tissues with mutational frequencies in cancer, we demonstrated that 5hmCs have lower mutation frequency than 5mCs.
While 5hmC in the DNA carry a benefit of reduce mutability, its presence in the nucleotide pool (used to synthesize new strands of DNA) is mutagenic. 5hmC and other biologically modified bases can enter nucleotide pool via recycling of epigenetically modified DNA. Our research on the metabolism of epigenetic nucleotides demonstrated that cytidine monophosphate kinase 1 (CMPK1) restricts production of 5hmdCTP and prevents incorporation of the modified base directly into DNA. However, cytidine deaminase (CDA) deaminates 5hmdC resulting 5hmdU, which is phosphorylated and incorporated into DNA, causing DNA damage. We are currently exploring whether this phenomenon can be exploited for personalised cancer therapy, targeting tumours overexpressing CDA.
Focused Screening Identifies Different Sensitivities of Human TET Oxygenases to the Oncometabolite 2-Hydroxyglutarate.
Belle R. et al, (2024), Journal of medicinal chemistry
Dysregulation of chromatin via H3K27 methylation underpins differentiation arrest in Isocitrate dehydrogenase-mutant Acute Myeloid Leukaemia
Silveira DRA. et al, (2023)
Modular Oxidation of Cytosine Modifications and Their Application in Direct and Quantitative Sequencing of 5-Hydroxymethylcytosine.
Xu H. et al, (2023), Journal of the American Chemical Society, 145, 7095 - 7100
Association between epigenetic heterogeneity of esophageal adenocarcinoma and response to first-line immunochemotherapy in LUD2015-005 Trial
Xie PF. et al, (2023), CANCER RESEARCH, 83
A critique of the hypothesis that CA repeats are primary targets of neuronal MeCP2.
Chhatbar K. et al, (2022), Life science alliance, 5