Nuclear Organisation and Oncogenesis - INSERM U.579  


  HEADDr DEJEAN Anne / adejean@pasteur.fr
  MEMBERSDr BISCHOF Oliver / CORDINA Emilie / DEMARQUE Maud / MARCHIO Agnès / Dr MARTIN Nadine / Dr OGRUNC Müge / Dr PINEAU Pascal / Dr PULLIRSCH Dieter/ Dr SEELER Jacob / Dr SCHWAMBORN Klaus / Prof TIOLLAIS Pierre


  Annual Report

The work in our lab is dedicated to the study of the molecular and cellular mechanisms involved in the development of human cancers with a particular emphasis on the role of certain post-translational modifications. To this end, a pluridisciplinary strategy that uses genetic, biochemical, cell and developmental biological tools are employed. Apart from the potential clinical applications, the study of the events underlying oncogenic transformation is also aimed at revealing novel fundamental biological processes in normal cells. Two distinct yet complementary approaches are taken.

Genetics and epigenetics of primary liver cancer

A first, 'global' approach seeks to establish a general profile of genetic, epigenetic or post-transcriptional alterations associated with hepatocellular carcinoma (HCC). To this aim : (i) mutational and functional analyses have been conducted for candidate tumor suppressor genes. (ii) we studied general and specific profiles of chromatin modifications, both at the histone and DNA levels, as well as the effects of deacetylase inhibitors (HDACi) in HCC cell lines. (iii) we initiated a comprehensive characterization of the main actors of epigenetic regulation (modifying/de-modifying enzymes, modifiers themselves, histone variants and miRNAs) in HCC. Notably, we identified 6 miRNAs specifically associated with HCC progression, the role of which will now be subject of further in-depth study.

Role of the SUMO pathway

A second, more 'mechanistic' approach, centers on the role of the SUMO pathway in both development and oncogenesis. The first approach aimed at identifying novel components associated with this pathway. We described two new SUMO targets, PARP1 and Ataxin-7, and identified the SUMO E3 ligase PIASy as an important co-regulator of FIP200 function in TSC/mTOR signaling. The second was devoted to study the role of sumoylation in vivo using animal models and derived cell cultures deficient/attenuated for sumoylation. We inactivated in a conditional manner the murine Ubc9 gene which encodes the unique E2 enzyme. Loss of sumoylation results in early embryonic lethality associated with severe defects in nuclear architecture and function (Figure). We have generated another mouse line harbouring a conditional ‘hypomorphic’ allele for Ubc9. We are identifying the organs and processes preferentially affected by the reduction in sumoylation at the level of the whole organism.

In parallel, we described a physical and functional interaction between PML, a major SUMO susbtrate, and the MAR-associated protein SATB1 in regulating chromatin loop architecture and transcriptional regulation. Finally, we described an important role for PIASy in telomere maintenance and cellular senescence. In this context, our goal is to elucidate the role of SUMO modification in chromatin regulation and more specifically in heterochromatin formation during cellular senescence

Keywords: Oncogenesis, Post-translational modifications, Epigenetics, Chromatin, Sumoylation, Cellular senescence, Liver cancer

Ono.jpg

Lack of sumoylation leads to major defects in nuclear structure and function



  Publications

Nacerddine, K., Lehembre, F., Bhaumik, M. Artus, J., Cohen-Tanoudji, M., Babinet, C., Pandolfi, P.P. and Dejean, A. 2005. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice, Dev. Cell, 9, 769-779.

Bischof, O., Nacerddine, K. and DejeanA. HPV oncoprotein E7 targets PML and circumvents cellular senescence via the Rb and p53 tumor suppressor pathways. Mol. Cell. Biol., 2005, 25, 1013-1024.

Bischof, O. *,, Schwamborn, K. *,, Martin, N., Werner, A.,, Sustmann, C., Grosschedl, R.andDejean, A. 2006. The E3 SUMO Ligase PIASy is a Novel Regulator of Cellular Senescence and Apoptosis.(* co-first authors). Mol. Cell, 22, 783-94.

Xhemalce, B., Riising, E.M., Baumann, P., Dejean, A.,Arcangioli, B. and Seeler, JS.Role of SUMO in the Dynamics of Telomere Maintenance in Fission Yeast. Proc. Natl. Acad. Sci. USA, 2007, 104:893-898.

Kumar, P.*, Bischof, O.*, Kumar Purbey, P., Notani, D., Urlaub, H., Dejean, A., and Galande, S.2007. Functional Interaction between PML and SATB1 Regulates Chromatin Loop Architecture and Transcription of the MHC class I Locus (* co-first authors). Nat. Cell Biol., 9, 45-56.





Activity Reports 2007 - Institut Pasteur
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