Stochastic modelling and estimation for the distribution of lengthening and abrupt shortening of ALT cells in yeasts

Biological context

Telomeres are nucleoprotein structures located at the ends of chromosomes, which they protect from degradation. During the cell division, the DNA is not entirely replicated leading to a loss of telomere sequences. Without any mechanism of telomere lengthening, telomeres progressively shorten until they reach a critical length (roughly at 70 bp in yeasts). Below this critical threshold, shortened telomeres trigger a permanent cell division cycle arrest, leading to a replicative senescence. This phenomenon is known as the end replication problem.

In the yeast Saccharomyces cerevisiae, telomere length homeostasis is the result of a balance between the action of the enzyme telomerase reverse transcriptase (TERT), which adds telomere sequences on short telomeres, and losses of telomere sequences due to the replication of DNA ends at cell divisions. As a result, telomere length varies from cell to cell and from telomere to telomere within a given cell, but stay of the order of 300 bp. When TERT activity is repressed, telomeres progressively shorten following the end replication problem until the replicative senescence. However, most often, in cultures of TERT-inactivated yeasts, rare “survivors” (roughly 1 among 100 000 individuals) escape senescence thanks to other telomerase-independent telomere maintenance mechanisms (called ALT for Alternative Lengthening of Telomeres), based in particular on homologous recombination.

ALT cells are characterized by very heterogeneous distribution of telomere lengths up to 10 kb. In ALT cells, telomeres are confronted with the end replication problem and therefore shorten with each cycle of cell division. Furthermore, as with natural telomeres, replication of ALT telomeres is a challenge to the cell’s replication machinery and therefore a source of stochastic replicative damage leading to abrupt shortening in the absence of telomerase. Finally, like natural telomeres, ALT telomeres are considered to be the preferential target of oxidative stress, which could be another source of abrupt telomere attrition.

Project description

The PhD project aims to develop a comprehensive model at the level of a population of lengthening and shortening of telomeres in ALT yeasts and to validate it on data of culture, giving the time evolution of the distribution of telomere lengths in the population.