Two projects are actually developed in the team :
1) Transcriptional regulation and mediator (Vincent Villeret)
Eukaryotic transcription regulation relies on co-activator complexes such as the SAGA or Mediator complexes. The Mediator is required for the regulation of mRNA transcription by Pol II. The mechanism of how Mediator enables regulated transcription is unknown, mainly due to limited structure-function information. Mediator is very large, comprising 25 subunits in yeast, with a total molecular weight of one mega-Dalton. Mediators in higher eukaryotes are larger than they are in yeast, with 30 or more subunits making up the human version. One feature of the mammalian Mediator is that its subunit composition is variable, raising the possibility that there are several versions, each one responding to a different, although possibly overlapping set of activators.
Our lab is studying the arrangement and organization of Mediator complex subunits to understand its possible architecture in higher eukaryotes. We are trying to decipher how different subunits contribute to the structural integrity of this complex. In particular, it is necessary to know how the higher eukaryote specific Mediator subunits, namely MED16, MED23, MED24, MED25 and MED26 interact with the core Mediator. We combine molecular, structural and cell biology in a multidisciplinary approach to elucidate the molecular bases of mammalian Mediator complex structural organization and assembly mechanism.
2) New functions of the oncoprotein Ets-1 (Marc Aumercier)
Ets-1 is the founding member of the family of transcription factors Ets. Ets-1 is mainly expressed in embryonic tissues. The pathological expression of Ets-1 is partly responsible for the proliferation and invasion abilities of tumor cells. Therefore, Ets-1 is currently considered as a marker of poor prognosis in several cancers. We recently demonstrated that Ets-1 interacts with enzymes involved in DNA repair and chromatin remodeling. The nature of these new partners strongly suggests new Ets-1 functions that have not been considered yet. Why Ets-1, a transcription factor recognized for its role in tumor progression, establishes interactions with DNA repair enzymes ? This discovery questions the role of Ets-1 as a pure transcription factor and suggests that it can also be involved in DNA repair and other “cryptic” functions.
Using the interdisciplinary approaches of molecular systems biology we aim to decipher the new functions of Ets-1. We want to i) characterize the new partners of Ets-1 that we have identified and validated in the tumor progression context ; ii) study the interaction between Ets-1 and these new partners using functional and structural approaches and iii) alter the interactions between Ets-1 and its new partners in order to evaluate their impact on the cancer cell phenotype.