Nuclear Organisation and Oncogenesis - INSERM U.579  


  HEADDr DEJEAN Anne / adejean@pasteur.fr
  MEMBERSDr BISCHOF Oliver / Dr PINEAU Pascal / Dr. SEELER Jacob / Pr TIOLLAIS Pierre Dr OGRUNC Müge / Dr SAHIN Umut / Dr MARTIN Nadine DEMARQUE Maud / NEYRET-KAHN Hélène / MARCHIO Agnès / ANDRIEUX Alexandra / DA Louise-Marie / GEORGES Monique / LEGUEULT Catherine / QUEROL Chantal.


  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. 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. Our work combines fundamental projects, based on experimental systems, as well as more clinically-oriented projects devoted to the study of human liver cancer.

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, (iii) we initiated a comprehensive characterization of the miRNAs differentially expressed in HCC. We identified a signature of 14 miRNAs specifically associated with HCC progression, the role of which is subject of further study.

Role of the SUMO pathway in healthy and diseased cells

A second, more 'mechanistic' approach, centers on the role of the SUMO pathway in both development and disease. The first axis aimed at characterizing novel components associated with this pathway. We identified PARP1 as a new SUMO target and describe a novel mechanism of regulation of PARP1 transcriptional activity through a sumoylation-coupled ubiquitination pathway. In parallel, we identified the SUMO E3 ligase PIASy as an important co-regulator of FIP200 function and provided the first evidence for the existence of a close, spatially controlled, interplay between PIASy and FIP200 in the regulation of TSC/mTOR signaling.

The second research axis was devoted to study the role of sumoylation in vivo using animal models deficient/attenuated for sumoylation. Homozygous inactivation of the SUMO E2 enzyme Ubc9 in mice results in early embryonic lethality associated with major nuclear defects (Figure). To further investigate the global role of sumoylation in vivo,

we have generated a series of mice in which expression of Ubc9 is reduced in a conditional and graded fashion from normal to zero by the use of various combinations of wild-type, hypomorphic and knock-out alleles (Ubc9+/+ > Ubc9+/H > Ubc9+/- > Ubc9-/H > Ubc9-/-). The elaboration of cellular and animal models deficient for sumoylation should now provide valuable tools for the elucidation of the general roles of this pathway in normal and disease-related fundamental processes.

Finally, we investigated the role of sumoylation and related modifications in cellular senescence and identified the deubiquitinating USP1 enzyme as a key player in this process. Moreover, preliminary experiments provide evidence for an involvement of small RNAs originating from DNA repeats in the establishment of the heterochromatin foci associated with senescence.

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

Ono.jpg

Lack of sumoylation leads to major nuclear defects



  Publications

Nacerddine, K., Lehembre, F., Bhaumik, M., Artus, J., Cohen-Tannoudji, 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 (Preview : Mol Cell, 2005, M. Kuehn) ; (Highlights : Nature Rev. Mol. Cel. Biol, 2006, R. Smallridge)

Bischof, O.*, Schwamborn, K.*, Martin, N., Werner, A., Sustmann, C., Grosschedl, R. and Dejean, A. (2006) The E3 SUMO ligase PIASy is a novel regulator of cellular senescence and apoptosis. (*co-first authors). Mol Cell. 22, 783-94.

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

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, 104, 893-898.

Martin, N*., Schwamborn, K*., Urlaub, H., Gan, B., Guan, J.L. and Dejean, A. (2008) (* co-first authors) Spatial interplay between PIASy and FIP200 in the regulation of signal transduction and transcriptional activity. Mol Cell Biol., 28, 2771-2781.





Activity Reports 2009 - Institut Pasteur
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