Acquiring new knowledge to decipher how cells divide, which is key to better understand the mechanisms of cancer, a disease caused by uncontrolled cell division.
Humans are roughly built from 10^13 cells corresponding to 200 different cell types. All these cells are generated through cell divisions, starting from a single cell, the fertilized egg. To generate these large number of cells and maintain tissue homeostasis, the human body experiences as many as 10^16 cell divisions in a lifetime. During each cell division, the genome must be faithfully replicated and equally segregated between the daughter cells during mitosis. Defects in these processes can have drastic consequences, leading to outcomes such as cell death, genome instability or deregulated growth, typical of cancer. Despite considerable progress, the mechanisms regulating cell division are incompletely understood. This lack of knowledge has considerably limited the development of innovative therapeutic approaches.
I- Mechanisms regulating mitotic entry in space and time
Commitment to mitosis must be tightly coordinated with DNA replication to preserve genome integrity. Consistently, unscheduled mitosis may contribute to genetic instability. Entry into mitosis is controlled by evolutionarily conserved serine/threonine kinases (Aurora A, Polo-like kinase, Plk1) as well as counteracting phosphatases (PPases). How these kinase activities are regulated in space and time, and how they work in concert to trigger mitosis at the right time remain ill defined. In this context, we are investigating the
- Activation mechanism of key mitotic kinases (Aurora A, Polo-like kinase 1)
- Role of mitotic kinases in nuclear envelope breakdown (NEBD)
- Role and regulation of Mitotic kinases during asynchronous cell division
Figure 1: Bora-Aurora A (Aurka)-Plk1 axis during mitotic entry
II- Role and regulation of the microtubule-severing enzyme Katanin
Microtubules (MTs) are dynamic cytoskeleton polymers, which play a central role in cell division, morphogenesis, motility and signaling. Most MT regulatory proteins interact with the plus or minus end of microtubules and thereby control their polymerization and depolymerization rates. However, one class of MT regulator interacts with the MT lattice and severs MTs throughout their length, thereby controlling their size and density in the cell. Three evolutionarily conserved MT-severing enzymes have been identified: Fidgetin, Spastin and Katanin. Mutations of these enzymes have been linked to various defects and pathologies including developmental defects and neurodegenerative disorders. However, little is known about the precise mechanisms by which these enzymes sever MTs. Likewise, how these enzymes are regulated in space and time is poorly understood. We are currently focusing on deciphering the mode of action and regulation of Katanin, which is essential for female meiotic spindle assembly in C. elegans. We are focusing our work on the
- role of MT-severing in meiotic spindle assembly
- Mechanism of MT-severing by Katanin
- Regulation of Katanin-mediated MT-severing in space and time during development
Figure 2: Role and regulation of Katanin during C. elegans development (From Joly et al. JCB 2020).
III- Cullin-RING E3-Ligases in cell division
Cullin-RING E3-ligases (CRL) represent the largest family of E3 ubiquitin-ligases targeting the degradation of key cell cycle regulators in space and time, contributing to the orderly progression of the cell division cycle. We are interested in understanding how these enzymes regulate cell cycle progression in a developmental context.
- CRL in the regulation of the Bora-Aurora-Plk1 pathway
- CRL in the regulation of Katanin activity
- CRL in the maintenance of DNA replication integrity
We use a multidisciplinary approach including biochemistry (reconstitution of enzymatic activities from purified components to dissect molecular mechanisms), genetics, live cell imaging, proteomics approaches using both human cells and the nematode C. elegans. Mechanisms regulating cell division are conserved between species such that emerging paradigm from C. elegans can be immediately investigated in human cells. Furthermore, C. elegans offers a number of practical advantages to study conserved pathways regulating cell division (Pintard & Bowerman, Wormbook, Genetics 2019).
Idex « AAP Dynamique » Université de Paris
Equipe Labellisée Ligue contre le Cancer
Frank SICHERI (University of Toronto, Canada)
Thierry LORCA (CRBM, Montpellier, France)
Anna CASTRO (CRBM, Montpellier, France)
Olivier GAVET (Institut Gustave Roussy, Paris Villejuif)
Mary DASSO (NIH, Bethesda USA)
Peter ASKJAER (CABD, Sevilla, Spain)
Verena JANTSCH (Max Perutz Labs Vienna, Austria)
Antoine JEGOU (Institut Jacques Monod, Paris, France)
Guillaume ROMET-LEMONNE (Institut Jacques Monod, Paris, France)
Denis CHRETIEN (IGDR, Rennes, France)
Julien DUMONT (Institut Jacques Monod, Paris, France)
Valérie DOYE (Institut Jacques Monod, Paris, France)
Bruce BOWERMAN (IMB, University of Oregon, USA)
Arshad DESAI (USCD, San Diego, USA)
Monica GOTTA (University of Geneva, Switzerland)