Presentation
Basic Research Team 1 « Telomere, senescence and cancer »
Pr Eric GILSON, PU-PH, Team Leader
Summary
Telomeres
Telomeres are key features of linear chromosomes that preserve genome stability. Variations in telomere state are critical for cell senescence, stem cell biology and the development of many diseases including cancer. They are composed of short tandemly repeated DNA sequences. The maintenance of this telomeric DNA depends on telomerase, a specialized reverse transcriptase that uses its RNA template to add G-rich telomeric repeats to the terminal 3’ overhang. The chromatin of telomeres is unusual, forming the so-called telosome. The telosome is essential to preserve chromosome stability by controlling telomere length, recombination and DNA damage checkpoint. A key component of the human telosome is the shelterin complex composed of six polypeptides (TRF1, TRF2, RAP1, Tin2, TPP1, Pot1) of which three bind directly to the telomeric DNA: TRF1 and TRF2 bind to the duplex telomeric DNA and Pot1 binds to the single strand 3’ overhang. In budding yeast, TRF1 and TRF2 do not exist and Rap1 is an essential capping factor that binds telomeric DNA.
The general aim of our project is to increase our knowledge on the basic mechanisms governing telomere functions and to explore their relevance in cancer. In brief, the objectives fall into three categories that can be described as :
- basic to understand the mechanisms that protect chromosome ends and to explore the signalization pathways sensing telomere state;
- oncogenesis-oriented to develop experimental models aimed at a better understanding of the role of telomere in cancer formation and progression and at screening and validating new pharmacological compounds targeting telomeres;
- clinically-oriented to explore telomere and telomerase functions in human cancer and to validate the benefit of telomere biomarkers in clinics.
Our experimental systems are yeast, as a basic model and screening resource, reconstituted in vitro systems, for an in-depth description of the molecular mechanisms of telomere functions, mouse, for xenograft and transgenic studies, policenormal human cells, immortalized lines, cancer cells, human cellular transformation systems and cancer tissues. The methodologies range from the biochemistry of telomeric nucleoprotein complexes to gene manipulations in human cells by retro- and lentiviral transductions, through various genetic, genomic and cellular analyses and functional exploration of telomeres in clinical samples. This diversity of approaches is justified by our aim to rapidly integrate basic concepts to clinically-oriented questions.
Research Project
Research Project
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Figure 1. The diversity of form and nature of telomeric components
(A) The diversity of form and nature of telomeric components sructure of intramolecular G-quadruplex structure of human telomeric DNA in K(+) solution. (B) G-quartet, detail of the structure above. (C) Schematic model of a t-loop. G-tail invasion and migration is thought to create a D-loop and a Holliday junction (shown in the two dotted circles) at the foot of the loop. (D), (E), (F) and (G) Schematic of main telomeric proteins in mammals, Saccharomyces cerevisiae, Oxytricha nova and Schizosaccharomyces pombe. The known structures of proteins and domains are shown. Secondary structures such as a-helices in TRF1, TRF2, RAP1and ScRap1 and ß-sheets in POT1, SpPot1,TPP1, Cdc13, TEBP, Stn1 and Ten1 are shown in red. |
Figure 2. TFR2 condenses telomeric DNA. RF2 condenses telomeric DNA Atomic force microscopy images of TRF2 complexes with a 650 pb telomeric duplex DNA. These complexes were shown to correspond to dimers, tetramers, hexamers and octamers of TRF2. Several molecules are shown in panels a and d. In panel a free DNA is also shown and in panel d, only the central molecule corresponds to the octameric form of the complex. Note the way DNA shortens with the increasing mass of the complex indicating DNA wrapping. Models of the complexes are drawn above the images. |
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Research Team
Research Team
GILSON Eric, PU-PH, Team LeaderTel : +33 (04) 93 37 77 93, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view itPatents
Patents
2007 - Eric Gilson, Alexandre Ottaviani :
« Polynucléotides insulateurs dérivés de l’élément D4Z4 et leurs utilisations en transgénèse »
Patent PCT/EP/2008/060004. Brevet N° 0756890 (2007) Lyon, France.
Financial Grants
Financial Grants
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Programs TELOREP, TELOLOOP, INNATELO, FSHDecrypt |
Program TELOFUN |
Program TELOMARKER |
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