Regulation of proliferative boundaries
Telomeres shorten as function of replication. When telomeres become critically short, they activate proliferative boundaries. In cells with functional damage checkpoints short telomeres induce terminal differentiation, termed senescence. In cells with dysfunctional checkpoint pathways senescence cannot be activated and telomeres shorten further, until they lose all protective properties. As a result, chromosomes start to fuse and breakage-fusion-bridge cycles ensue, leading to replicative crisis. During replicative crisis most cells in a population die, thereby preventing the evolution of cancerous cells with unstable genomes. We are interested in understanding the triggers for replicative crisis, and how telomere shortening, fusion and breakage activate crisis.
Telomeres, due to their repetitive sequence and structure present obstacles to the replication machinery. Telomeric replication dysfunction can lead to telomere shortening or telomere loss, leading to increased risk of accelerated aging or genome instability. We are interested in telomere-specific functions and components of the replication machinery, and how accurate telomere replication contributes to genome stability.
Evolution of genome stability during cellular aging
The evolution of cancer cells is often coupled to an unstable genome and cancer cells are frequently defined by aneuploidy and genome instability. We are studying what role telomeres, telomere shortening and telomere fusion play in the evolution of genome instability, by in depth analysis of individual cells on their journey from normal to cancerous cells.
Telomere function, inflammation and autophagy
We have discovered that cells in replicative crisis activate autophagy, which eliminates such cells, thereby acting as age-associated tumor suppressive pathway. We are interested in the pathways connecting telomeres and autophagy, how critically short telomeres activate cell-lethal inflammation, how this inflammation activates autophagy, and what autophagy targets are specific to cells suffering from telomere dysfunction.
Cancer prevention by telomere driven autophagy in vivo
Based on our discovery that autophagy eliminates cells with critically short telomeres from the population, we hypothesize that autophagy serves as a tumor suppressor during the earliest stages of cancer initiation. We are investigating the underlying pathways by generating models for telomere and autophagy dysfunction in vivo.