Preservation and regulation of genetic information is essential for proper cell function. Consequently, cells have evolved mechanisms of DNA repair, telomere maintenance, and epigenetic regulation of gene expression patterns. These processes are functionally linked and converge on chromatin, the complex structure formed by DNA and associated proteins, in the nucleus of eukaryotic cells.
Deregulation of these processes contributes to the appearance and progression of cancer cells, which are characterized by genomic rearrangements and dysregulated gene expression patterns.
1. DNA damage repair in fission yeast S. pombe: DNA repair processes have been well conserved throughout evolution, and yeast has proven to be a good model for their study. We use S. pombe to dissect the mechanisms of DNA double-strand break (DSB) repair, a type of genetic lesion arising after exposure to genotoxic agents or during DNA replication. We focus on improper DSB repair resulting from either deletion or insertion of nucleotides at the repair junction.
2. Mechanisms of telomere maintenance: Telomeres are specialized protein-DNA structures, which prevent chromosome ends from being recognized as DSBs. Synthesis of telomeric DNA sequences in replicating cells requires telomerase. Cancer cells often show an increased level of telomerase, and this contributes to their unlimited proliferation potential. Certain tumor cells however lack telomerase, and rely on an alternative mechanism (ALT) to maintain their telomeres. We are comparing telomerase-positive and -negative human cell lines to get more insight into the ALT mechanism and to dissect the “non-canonical” functions of telomerase that are not directly related to telomere repeat addition but modulate cellular gene expression. We are also interested in studying the role of subtelomeric DNA methylation in the maintenance of telomeres.
3. DNA hypomethylation and aberrant gene activation in cancer: DNA methylation is an essential mechanism of epigenetic regulation. It is associated with gene repression. Virtually all tumor cells show widespread loss of DNA methylation. We have found that this alteration results in the activation of a set of genes, which are normally restricted to the germ line. We are currently investigating the mechanisms targeting DNA demethylation towards these “cancer-germline” genes in tumor cells.
4. Setting of DNA methylation patterns in embryonic stem cells : Embryonic stem cells are characterized by a remarkable epigenetic plasticity. The processes underlying the setting of DNA methylation patterns in these cells are studied, with a particular emphasis on cancer-germline gene promoters.