CV Science

Maria Teresa TEIXEIRA PhD Life Sciences

Course and current status

MTT’s main focus is the study of telomere shortening mechanisms and their consequences for cell proliferation ability, namely, the control of replicative senescence. She has provided evidence for the first telomere reaching a critical short length being the major determinant of the onset of senescence in budding yeast. Then, her team identified the signal of senescence as being the accumulation of ssDNA at the shortest telomere and uncovered a role of replication stress response at telomeres, through Rad5, a factor of the DTT pathway involved in the replication of difficult templates. In a second axis, the team focused on the mechanism of telomere shortening in the absence of telomerase and elucidated the DNA-end replication problem. Together with a biophysicist, they developped microfluidics devices to assess replicative senescence in single-cell lineages. This approach lead not only to define the dynamics of the cellular response to the gradual shortening of telomeres, but also revealed a cryptic route to senescence prone to genomic instability. Mathematical modelling of senescence in collaboration with mathematicians revealed components of cell-to-cell variability in senescence and showed how intrinsic properties of telomere replication contribute to generate phenotypic variants.

MTT obtained her PhD in Life Sciences from the University Paris Sud-Orsay in 2000. For her postdoc, she joined the laboratory of Joachim Lingner at the ISREC in Lausanne. She obtained a CNRS position in 2005, appointed to the lab of Eric Gilson in Lyon. MTT started her lab in 2010.

Scientific summary

Telomeres are the ends of eukaryotic chromosomes. They are composed of GT-rich repeated sequences, which are transcribed into non-coding RNAs and recruit specific proteins to protect DNA ends from fusions and degradations. This occurs mainly by preventing the DNA damage response (DDR) pathway from fully operating at telomeres. Telomeric sequences are lost at each passage of the replication fork and re-elongated by telomerase. In absence of this enzyme, telomeres shorten progressively at each cell division leading to a cell cycle arrest, which depends on the activation of the DDR at the shortest telomere(s). In many vertebrates, including humans, most somatic tissues do not express telomerase, telomeres shorten gradually, causing replicative senescence. In contrast, in mice, telomerase is active, and senescence has other causes. Still, the telomere shortening-dependent senescence phenotype can be recapitulated in mice or model unicellular eukaryotes in which telomerase is experimentally removed. Overall telomeres provide a unique mechanism to limit the lifespan of eukaryotic cells. In cancers, this pathway is eluded to allow limitless proliferation: the signaling of senescence is bypassed and, subsequently, telomere reduction is counteracted by abnormal re-elongation of telomeres. However, the mechanisms underlying these transitions are largely unknown.

An inherent difficulty in studying telomere biology is the heterogeneity resulting from intracellular differences in the length and status of telomeres and the immense intercellular variations in telomere-related phenotypes such as replicative senescence. Moreover, averaging data from heterogeneous cell populations results in biased models that often stand as enduring dogmas. Conversely, differences in telomere lengths and status might well be the source of cell-to-cell variations in replicative senescence onset, but this has not been extensively investigated. We thus propose to dissect the structure of telomeres at the single-molecule level and to connect this to the capacity of single cells to divide.