Telomeres are heterochromatic nucleoprotein structures located at the tips of linear eukaryotic chromosomes. Telomeres allow cells to distinguish between natural chromosome ends and double-stranded breaks in the DNA and also set the lifespan of normal somatic cells by eliciting cellular senescence when they become critically short. Loss of proper telomere structure triggers severe chromosomal instability cascades that are hallmarks of many human diseases including cancer.
The heterochromatic nature of telomeres and their gene-less nature suggested the notion that telomeres are transcriptionally silent genomic regions. On the contrary, we discovered that eukaryotic chromosome ends generates an intricate array of RNA molecules, including the long non-coding RNA TERRA (telomeric repeat-containing RNA). TERRA molecules are transcribed from several subtelomeric loci towards chromosome ends and remain associated to telomeres post-transcriptionally. We have also shown that the human helicase UPF1, which is a key effector of an RNA surveillance pathway known as ‘Nonsense-Mediated mRNA Decay’ (NMD), is enriched at telomeres in vivo, negatively regulate TERRA association with chromatin and promotes complete replication of telomeric DNA.
Our laboratory exploits a variety of molecular genetic, biochemical and cell biological approaches in order to characterize TERRA structure and function, using cultured mammalian cells and fission yeast as model systems.
We are currently addressing crucial questions about TERRA biogenesis and putative TERRA-associated functions in maintaining telomere architecture in normal, cancer and senescent cells. We are also trying to dissect the molecular events leading to accumulation of telomere-associated TERRA and to telomere dysfunctions in cells compromised for UPF1 function. With these goals, we hope to expand the current understanding of how normal telomere structure is maintained and to unveil novel cellular pathways involved in cancer and senescence etiology.
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