Telomeres and cellular senescence

Research project

Our group studies the physiological consequences of the activation of the DNA damage response at the cellular and organismal level.

In mammals, DNA damage in the nucleus triggers a coordinate set of events known as the DNA damage response (DDR). DDR can ultimately force a damaged cell to become senescent. Senescent cells are metabolically alive yet unable to proliferate.

Fig 1: Mouse metaphase chromosomal spreads. DNA is in blue, telomeric TTAGGG repeats are in yellow.

The proliferative block imposed by cellular senescence has been proposed to play a role in aging and it has been shown to be a powerful tumor suppressive mechanism - see our recent review on cellular senescence.

Replicative senescence, the inability of normal mammalian cells to proliferate indefinitely under appropriate growth conditions, can be the consequence of telomere erosion. Telomeres are the tips of linear chromosomes. We have previously shown that critical telomere shortening triggers a DDR that arrests cell proliferation and causes cellular senescence. We are now investigating in further depth the molecular mechanisms controlling this type of cellular senescence.

We are also intrigued by the role of DDR factors in telomere homeostasis beside the senescence condition. Our work showed that the DDR complex Rad9/Rad1/Hus1 controls telomere length in mice and we propose it may do so by its ability to modulate telomerase activity.

Fig 2: Fluorescence microscopy image of a senescent cell expressing oncogenic Ras: the phosphorylated form of histone H2AX (γ-H2AX) is stained in green and the DNA damage checkpoint protein 53BP1 is in red, DNA is in blue.

Cellular senescence can also be the result of oncogene activation. We recently discovered that expression of an activated oncogene (H-Ras) triggers a robust DDR that halts cell cycle progression. Cells unable to mount a proficient DDR do not senesce and proliferate, despite the accumulation of DNA damage. Our results suggest that the alteration of the DNA replication process by activated oncogenes is crucial for DNA damage generation. We are now studying the impact of oncogene activation on the DNA replication process and the mechanisms that lead to the establishment of cellular senescence and its maintenance.
Our observations, made in cultured cells, can be recapitulated in vivo, both in mice and in humans. In patients, we have observed the complex engagement of DDR in various tumors and characterised its stepwise inactivation during cancer progression.

More recently, we contributed to the realization of an unexpected link between DDR signaling and inflammation: we observed that some cytokines are positive regulators of DDR signaling and cellular senescence.
It is now recognized that DDR genes control the secretion of some cytokines, generating a positive feedback loop.

The worm Caenorhabditis elegans provides a beautiful system to study the modulation of DDR at the organismal level during development and aging. We are presently exploring how DDR can be activated in the different tissues and compartments of this animal and the impact of its activation.