DS0405 -

Prepare Your Separation: Molecular Characterization of a Novel Telomere Disjoining Pathway, a Driven Force for Mitotic Completion – TeloMito

Submission summary

The accurate transmission of the genetic material throughout cell divisions is essential for all living organisms. Defective chromosome transmission can lead to irreversible abnormalities in the structure and/or the number or chromosomes, leading to genetic pathologies. Understanding the mechanisms of chromosome transmission is therefore a major goal of Biological and Biomedical research. In eukaryotes, accurate chromosome segregation during mitosis relies on the bilateral attachment of mitotic chromosomes to the mitotic spindle via their centromeres, and the separation of sister-chromatids towards the opposite poles of the spindle. During the past century, considerable efforts were made to understand spindle assembly and centromere attachment. Meanwhile, several studies reported that telomeres and/or the integrity of telomeric heterochromatin play an important role in the accurate segregation of chromosome arms. Yet, the underlying mechanisms (active or passive) through which telomeres contribute to chromosome segregation remained elusive. We recently described a novel and essential pathway that promotes telomere dissociation in mitosis. This pathway involves the chromosomal complex condensin and the Aurora B kinase to complete mitosis through the efficient separation of chromosome ends. The objective of this proposal is to further decipher the molecular mechanisms through which this hitherto ignored Telomere Disjoining Pathway (TDP) promotes chromosome segregation. For that, we propose to identify how Aurora-B connects condensin and telomeric proteins to set up the efficient and timely separation of telomeres. We also aim to understand what is the precise function of telomeres and telomeric proteins in chromosome segregation. To decipher the mechanisms of TDP we will employ multiscale and interdisciplinary approaches, starting from the analysis of protein complexes at the chromatin level, to end with state of the art system cell biology approaches. Our three-team consortium brings the complementary expertise for that project and is operational since it has already gathered preliminary data. The project will be performed using the fission yeast Schizosaccharomyces pombe as a model system, which is renowned for studying chromatin structure, cell cycle and chromosome segregation. Aberrant variations in telomere state are critical for cell senescence, stem cell biology and the development of many diseases, including dyskeratosis congenita, Hooyeraal-Hreiderarsson syndrome and Coats plus syndrome. Chromosomal and genetic pathologies are responsible for severe health problems with important social and economic consequences. Hence, studying new and fundamental mechanisms that operate at telomeres to ensure accurate chromosome segregation constitutes a real challenge in cell biology and for human life.

Project coordination

Sylvie TOURNIER (Laboratoire de Biologie Moléculaire et Cellulaire du Controle de la Prolifération; Centre de Biologie Intégrative)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LBMC - CNRS Pascal Bernard
CNRS DR12 - UMR7258 Centre National de la Recherche Scientifique délégation Provence et Corse_CNRS 7258
LBCMCP (CBI) Laboratoire de Biologie Moléculaire et Cellulaire du Controle de la Prolifération; Centre de Biologie Intégrative

Help of the ANR 504,351 euros
Beginning and duration of the scientific project: September 2016 - 36 Months

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