RAD51 dans les mouvements en miroir congénitaux : une recombinase de l'autre coté du miroir - Sorbonne Université Access content directly
Habilitation À Diriger Des Recherches Year : 2021

RAD51 in congenital mirror movements: a recombinase through the looking glass

RAD51 dans les mouvements en miroir congénitaux : une recombinase de l'autre coté du miroir

Abstract

As a student, I was interested in understanding the links between cellular functions and the underlying molecular mechanisms. In accordance with my university training in molecular and cellular biology (ENS Paris), my PhD work in C. Mann’s team (CEA/Saclay; 2000-2003) was thus dedicated to the study of signaling pathways in the DNA damage response of the model yeast, Saccharomyces cerevisiae. We first demonstrated a new role for the Sgt1 protein as a co-chaperone of an adenylate cyclase (Dubacq et al., 2002). We then identified new pathways activated in response to the genotoxic drug hydroxyurea, involving the stress response Snf1 kinase (Dubacq et al., 2004) and the redox-responsive Yap1 and iron- mobilization Aft1/2 transcription factors (Dubacq et al., 2006). For my first postdoctoral position, as an assistant professor (ENS Paris, 2003-2008), I joined A. Trembleau in the A. Prochiantz’ team, to develop a new project on more integrative questions. There, I set up the study of local axonal translation of olfactory receptor mRNAs in the olfactory sensory neurons in mice, which was part of a larger project addressing the role of these receptors in axon guidance to form the discrete primary olfactory map (Nedelec et al., 2005). After our move to Sorbonne University, I obtained my present permanent position as a full-time assistant professor (2008) and we continued to address these questions with the financial support of ANR (2010) and NIH (2013-2017; collab. C. Greer). With S. Jamet (M2 student), we demonstrated that the axonal olfactory receptor mRNAs were actually associated with polysomes in a developmentally regulated way (Dubacq et al. 2009). In addition, local translation was evidenced in the olfactory dendrites (Persuy et al., 2011; collab. C. Baly). I then focused on potential regulation factors for olfactory receptor mRNAs. During J. Chareyre M2 internship, we studied the involvement of the RNA binding protein FMRP in olfactory neurons (collab. B. Bardoni). Thanks to C. Cros and with the help of 2 other M2 students, we recently demonstrated that olfactory receptor mRNAs are subject to a massive alternative polyadenylation, opening new avenues to study the cis regulatory sequences in their 3’ untranslated regions (Doulazmi et al. 2019; collab. M. Doulazmi, D. Logan, S. Firestein). The team also showed that these receptors may have adhesion properties in line with a putative role in axon sorting (Richard, Jamet et al., 2013, Dubacq et al., 2014). Since the late 2010ies, I’m interested in the role of the RAD51 DNA repair protein in the axonal guidance of cortico-spinal neurons. This second study is part of the MoMiC project, supported by an ANR grant (2018) and directed by I. Dusart (our team) and E. Roze (Institut du Cerveau), aiming at understanding the physiological and molecular bases of the lateralization of voluntary movements in mice and humans. It overlaps the PhD work of O. Trouillard done under my supervision. Unexpectedly, RAD51 mutations are found in patients with Congenital Mirror Movements (Trouillard et al., 2016). My objectives are thus to dissect the RAD51 molecular functions necessary for its new cytoplasmic role in the nervous system (collab. R. Guérois & J. Andreani, S. Lambert, G. Rodrigues & J. Guirouilh-Barbat, P. Dupaigne & E. Le Cam). With M. Dunoyer (M2 student), we proved oligomerization defaults of the CMM-RAD51 loss-of-function mutants. We now plan to analyze RAD51 subcellular localization and partners, as well as the morphological changes due to mutated RAD51 expression in mouse neurons. In the same project, we previously showed that the NTN1 mutations found in CMM patients were associated with a decreased secretion of the netrin-1 guidance cue (Méneret et al., 2017; collab. A. Chedotal). Aside these 2 projects, I’m part of other studies in the team (Daroles et al. 2016, Stoufflet et al., 2020; collab. I. Caillé) or in the institute (Dufor et al., 2019; collab. R. Sherrard).
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tel-04043566 , version 1 (27-03-2023)

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Caroline Dubacq. RAD51 dans les mouvements en miroir congénitaux : une recombinase de l'autre coté du miroir. Sciences du Vivant [q-bio]. Sorbonne Université, 2021. ⟨tel-04043566⟩
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