Deciphering how telomere-binding protein controls telomere length homeostasis

The internship will take place within the UMR Genetic Stability, Stem Cells and Radiation (SGCSR), part of the François Jacob Institute of Biology at CEA. The unit brings together research teams working on DNA repair, genome stability, stem cell biology and cellular responses to genotoxic stress. It combines complementary expertise in molecular and cellular biology, using model organisms such as Saccharomyces cerevisiae, as well as human and mouse cell models. The UMR is jointly supported by CEA, Université Paris-Saclay and Inserm and is located at the CEA site in Fontenay-aux-Roses.

Internship description

Introduction: Telomeres are specialized nucleoprotein structures that cap the ends of linear chromosomes, protecting them from being recognized as broken DNA [e.g.: Mattarocci et al. 2025, 2026].  Telomeres also permit controlled, length-dependent access of telomerase to counteract replication-dependent shortening of the chromosome ends. In human germlines, this telomere length homeostasis sets the initial telomere length of telomerase-negative somatic cells, which then shorten with each division. When telomeres reach a critically short length, they limit replicative lifespan and contribute to ageing and cancer suppression. Cancer cells often reactivate telomerase to bypass this telomere-driven proliferative limit. Telomere length homeostasis is thus a conserved process central to the balance between replicative lifespan and cancer suppression. How telomeres sense their own length and translate this information into quantitative control of telomerase activity remains largely unknown.

Telomeres are bound by sequence-specific proteins (Rap1 in budding yeast; TRF1/TRF2 in mammals) that limit the access of both DNA damage response factors and telomerase. This internship will exploit the genetic and molecular tractability of budding yeast cells to dissect the mechanisms by which telomere-binding proteins quantitatively control telomere elongation.

Aim of the project: The student will use engineered and native yeast telomeres to ask how telomere-protein influences the activation and termination of telomerase-mediated elongation.

Significance: This project will help defining the diversity of mechanisms by which telomere-bound proteins reconcile two crucial tasks — hiding a natural DNA end from repair pathways while still permitting its regulated, gradual elongation. Because the core protein complexes involved are conserved from yeast to humans, the expected findings will inform our understanding of genome stability, ageing and cancer.

Model organism used: Saccharomyces cerevisiae

Techniques used during the internship

The student will use yeast genetics and molecular biology (strain construction, inducible DSB/telomere systems), nanopore sequencing of individual telomeres, TdT-PCR/qPCR and chromatin immunoprecipitation (ChIP) to monitor repair/elongation events and protein binding. The internship could also include biochemical/biophysical characterization of protein–DNA interactions. Overall, the student will acquire a broad and diverse skill set spanning yeast genetics, genomics, and biochemistry, applied to the study of genome stability. The student will also develop bioinformatics skills, especially for the analysis of nanopore sequencing data of repeated sequences.

Bibliography:

Mattarocci S, Baconnais S, Roisné-Hamelin F, Pobiega S, Alibert O, Morin V, Deshayes A, Veaute X, Ropars V, Chevreuil M, Mehringer J, Busso D, Mazon G, Fernandez Varela P, Le Cam É, Charbonnier JB, Cuniasse P, Marcand S. (2025) Nat Commun. 16(1):6824.

Mattarocci S, Reginato G, Cannavo E, Roisné-Hamelin F, Gnügge R, Deshayes A, Pobiega S, Alibert O, Morin V, Ropars V, Mehringer J, Geli V, Cuniasse P, Charbonnier JB, Symington L, Cejka P, Marcand S. (2026) Rap1-Mediated Steric Hindrance Prevents DNA End Sensing by MRX to Protect Telomeres. Nat Struct Mol Biol. 33(6):915-927.

Master’s student in biology, molecular biology, genetics or a related field, with an interest in genome stability and DNA repair. Basic knowledge of molecular biology and genetics is appreciated. The candidate should be motivated, curious and willing to learn new experimental approaches. Previous laboratory experience is an advantage, but is not required.