iGReD - Telomeres and cancer

Published on July 21, 2021 – Updated on July 23, 2021

All cancer cells absolutely require reactivation of telomere maintenance mechanisms in order to proliferate. We currently study the telomeric CST complex (Cdc13-Stn1-Ten1) in a model system, the yeast S. cerevisiae. In addition, we collaborate with clinicians by measuring telomeric parameters in tumor samples.

Genomic DNA from tumor samples is incubated with the Phi29 DNA polymerase, which amplify the partially single-stranded ALT-specific extrachromosomal telomeric DNA circles. DNA from HeLa cells (telomerase +) and U2OS cells (ALT +) serve as co

Genomic DNA from tumor samples is incubated with the Phi29 DNA polymerase, which amplify the partially single-stranded ALT-specific extrachromosomal telomeric DNA circles. DNA from HeLa cells (telomerase +) and U2OS cells (ALT +) serve as co

In all cancer types, cell division and proliferation are associated with the acquisition of the capacity to maintain functional telomeres (the extremities of linear chromosomes). Telomeric DNA is replicated by a specialized reverse transcriptase, called telomerase. In addition, telomeres recruit specialized proteins that form a protective cap, thus preventing against degradation. In Vertebrates, these functions are mainly taken in charge by the so-called shelterin complex, composed of the TRF1, TRF2, POT1, TIN2, TPP1 and RAP1 proteins. Shelterin is also present in the yeast S. pombe, but not in the yeast S. cerevisiae, in which its functions are mainly insured by the CST complex (Cdc13-Stn1-Ten1). However, surprisingly, the CST complex was also, only recently, identified in humans, mouse and plants, as well as in many other eukaryotes.

Our main contribution to the telomeric field has been to identify, in S. cerevisiae, Stn1 and Ten1 of the CST complex and to demonstrate that, together with Cdc13, they are essential for telomerase recruitment, as well for telomere end protection. We currently use classical molecular biology and genetics methods and occasionally have recourse to genome-wide techniques, such as mass spectrometry and RNA-seq. Our studies have also allowed to uncover novel functions for CST, such as in the regulation of RNA Pol II transcription. Globally, our main objective is to study the fundamental molecular mechanisms and pathways used by eukaryotic cells to maintain genome stability through the maintenance of functional telomeres.

Since telomerase reactivation and the maintenance of functional telomeres is essential for the proliferation of cancer cells, we have, during the last ten years or so, and in parallel with our studies on yeast, studied human telomeres in cultured cells, as well as in tumor samples from patients suffering from gliomas or colorectal cancers, in collaboration with clinicians. We are, in particular, interested by the mechanisms underlying the ALT pathway, a telomerase-independent pathway based on homologous recombination between repeated telomeric DNA sequences that functions in some cancer subtypes.