Axis 1, Team 6 | Protein structure and function in normal and pathological tissues

Structure/function analysis of the estrogen receptor ESR1

Breast cancer is the most common cancer in women. Prolonged exposure to endogenous or exogenous estrogens is one of the primary causative factors of hormone-dependent breast cancer. Indeed, >70% of breast cancers express the estrogen receptor (ER, encoded by ESR1) and are under the influence of the mitogenic effects of estrogen. Hormone therapy is the most effective treatment used to treat ER-positive breast cancer. A significant proportion of breast cancer resist hormone therapy or develop resistance to antiestrogens such as tamoxifen. Our research aims to understand the origin of this hormonal resistance by studying the genetic and epigenetic mechanisms controlling the conformation of the receptor and the associated functional properties.

Project leader: Gilles Flouriot

Participants: Frédéric Percevault, Farzad Pakdel, Pascale Le Goff, Denis MichelLéa Clusan

Relevant publications: PubMed

Funding: Inserm | Université de Rennes 1 | La Ligue Contre le Cancer

Collaborations: Raphael Metivier and Christophe Tiffoche (IGDR, Rennes); Jean-François Arnal (I2MC, Toulouse); Tamara Fernandez-Calero (Institut Pasteur, Montevideo, Uruguay); Reynald Gillet (IGDR, Rennes), Daniel Henrion (MITOVASC, Angers).

Posttranslational regulation of EXOSC10/Rrp6

The highly conserved 3'-5' exoribonuclease EXOSC10 (Rrp6) processes and degrades coding and non-coding RNA, controls gene expression and is required for DNA double-strand break repair and  telomere maintenance. The enzyme is associated with the nuclear RNA exosome and interacts with numerous proteins. Clinical, genetic, biochemical and genomic anlyses provided insights into the protein's critical roles in mitotic cell division and meiotic differentiation, identified its RNA substrates and associated the protein with autoimmune disorders and cancer. We are interested in molecular mechanisms that control the stability of EXOSC10/Rrp6 during growth and development of normal and cancer cells. To this end, we are investigating mutant alleles that may alter the conformation and/or activities of EXOSC10/Rrp6.

Project leader: Michael Primig

Participants: Florence Demay, Yann Le Page

Relevant publications: PubMed

Funding: Inserm | Université de Rennes 1 | La Ligue Contre le Cancer

Collaborations : Antonin Morillon (Curie Institute, Paris, France); Ronald W Davis (Stanford University, Palo Alto, USA); Igor Stuparević and Ana Novačić (University of Zagreb, Croatia); Michael Law (Stockton University, Galloway, USA). 

Protein structure and molecular assembly in cancer and neurodegenerative diseases

We analyze the structure and macromolecular assembly of proteins involved in neurodegenerative diseases or breast cancer. MAPT is important for microtubule assembly and stability and neuronal polarity. HSP90 plays a role in the self-assembly of amyloid peptides and proteins and the progression of breast cancer.

Project leader: Cyrille Garnier

Participants: Gilles Flouriot

Relevant publications: PubMed

Funding: Inserm | Université de Rennes 1 | European Union | Bretagne Valorisation

Collaborations: Sandrine Huclier (Subatech, Université de Nantes, France); Christel Marquette (U1292 BIOsanté, CEA, France); Renata Miolajczak (National Centre for Nuclear Research, Poland); Dana Niculae (Horia Hulubei National Institute for Physics and Nuclear Engineering, Romania); Petr Hermann(Universita Karlova, Czech Republic); Tomasz Dziel (Centrum Wysokich Technologii w Świerku Hitec Świerk Sp. Z o.o, Poland)