Epigenetics and DNA Repair

Genome and epigenome stability

Our research is focused on the study of genome and epigenome maintenance mechanisms. DNA repair is essential for correct cell function, and defects in DNA repair pathways are responsible for a significant number of pathological conditions, including cancer. Alterations of normal epigenetic patterns have important physiological consequences and are also key components of disease. Recent results obtained by our group and other laboratories have uncovered unexpected roles for DNA repair mechanisms in the epigenetic control of gene expression and in embryonic development. Following up on these exciting findings will be a major focus of our future research.

DNA methylation is a reversible epigenetic mark

Methylation of cytosine at carbon 5 of the pyrimidine ring (5-meC) is an epigenetic mark for transcriptional gene silencing, and plays important roles in controlling cellular differentiation and proliferation, gene expression, genomic imprinting, X-chromosome inactivation and genomic instability. Distortion of DNA methylation patterns is a central component in many forms of human disease. In particular, aberrant DNA methylation is usual in many types of human cancer. Cancer cells usually display a globally hypomethylated genome punctuated by local hypermethylation at promoters of tumour suppressor genes. Transcriptional repression arising from this local hypermethylation is thought to play an essential role in the tumorigenic process. DNA methylation is a dynamic process that can be reversed by active demethylation mechanisms. Despite dramatic progress in epigenetics during the past decade, DNA demethylation remains one of the last big frontiers and very little is known about it. Understanding how the methylation status of the genome is regulated requires the biochemical definition of the enzymatic processes that demethylate DNA.

DNA demethylation involves a DNA repair mechanism

Work carried out by our research group and other laboratories has provided convincing genetic and biochemical evidence that a family of DNA glycosylase domain-containing proteins typified by Arabidopsis ROS1 (REPRESSOR OF SILENCING 1) and DME (DEMETER) initiates erasure of 5-meC through a base excision repair process. We have characterized the biochemical activity of this family of enzymes and have identified other proteins implicated in this new mechanism of epigenetic reprogramming. We are now investigating the relevance of DNA repair mechanisms to the maintenance and dynamics of the genome and epigenome. Our major goal is to translate the knowledge generated from the study of this family of DNA glycosylases to increase our understanding of the epigenetic reprogramming that takes place in processes such as the generation of stem cells and tumour development and progression in humans.