Kriaucionis Group Research Overview
Cytosine in DNA can be a substrate of three groups of modifying enzymes: methyltransferases, dioxygenases and deaminases. The first two of these generate cytosine variants that are important in regulation of gene expression or repair the damaged base, whereas deamination changes the identity of the base, resulting in mutations. Cancer cells have both numerous mutations and abnormal patterns of DNA modifications. Typically, in cancer 5-methylcytosine (5mC) appears on the promoters of some genes and decreases in intergenic regions. All cancers have depleted 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Whilst the many of the mechanisms of the most frequent mutations in cancer have been well-explored, the contribution of defective DNA modifications to transformation is poorly understood. Evidence that altered DNA modifications are not just a passive reflection of a change in the phenotype of cancer cells comes from the observation of frequent mutations in the genes encoding the DNA methyltransferase DNMT3A and dioxygenase TET2 in some blood cancers. Yet even in these cancers, the links between mutated enzymes and cancer phenotypes are unknown. In addition, errors in epigenetic inheritance of DNA methylation, guided by stochastic and deterministic components, could affect the risk of cancer. By studying the dynamics and function of DNA modifications in normal organisms and in cancer cells, we aim to advance the understanding of how DNA modifications contribute to cancer and to identify key nodes for epigenetic intervention.
- To reveal the role of the metabolism of DNA modifications in cancer risk and discover new routes for therapy.
- To elucidate the effects of and mechanisms by which DNA modifications affect mutability of DNA.
- To reveal the principles of how DNA modifications affect transcription.