Project acronym DNATRAFFIC
Project DNA traffic during bacterial cell division
Researcher (PI) François-Xavier Andre Fernand Barre
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary The molecular mechanisms that serve to couple DNA replication, chromosome segregation and cell division are largely unknown in bacteria. This led a considerable interest to the study of Escherichia coli FtsK, an essential cell division protein that assembles into DNA-pumps to transfer chromosomal DNA between the two daughter cell compartments during septation. Indeed, our recent work suggests that FtsK might regulate the late stages of septation to ensure DNA is fully cleared from the septum before it is allowed to close. This would be the first example of a cell cycle checkpoint in bacteria.
FtsK-mediated DNA transfer is required in 15% of the cells at each generation in E. coli, in which it serves to promote the resolution of topological problems arising from the circularity of the chromosome by Xer recombination. However, the FtsK checkpoint could be a more general feature of the bacterial cell cycle since FtsK is highly conserved among eubacteria, including species that do not possess a Xer system. Indeed, preliminary results from the lab indicate that DNA transfer by FtsK is required independently of Xer recombination in Vibrio cholerae.
To confirm the existence and the generality of the FtsK checkpoint in bacteria, we will determine the different situations that lead to a requirement for FtsK-mediated DNA transfer by studying chromosome segregation and cell division in V. cholerae. In parallel, we will apply new fluorescent microscopy tools to follow the progression of cell division and chromosome segregation in single live bacterial cells. PALM will notably serve to probe the structure of the FtsK DNA-pumps at a high spatial resolution, FRET will be used to determine their timing of assembly and their interactions with the other cell division proteins, and TIRF will serve to follow in real time their activity with respect to the progression of chromosome dimer resolution, chromosome segregation, and septum closure.
Summary
The molecular mechanisms that serve to couple DNA replication, chromosome segregation and cell division are largely unknown in bacteria. This led a considerable interest to the study of Escherichia coli FtsK, an essential cell division protein that assembles into DNA-pumps to transfer chromosomal DNA between the two daughter cell compartments during septation. Indeed, our recent work suggests that FtsK might regulate the late stages of septation to ensure DNA is fully cleared from the septum before it is allowed to close. This would be the first example of a cell cycle checkpoint in bacteria.
FtsK-mediated DNA transfer is required in 15% of the cells at each generation in E. coli, in which it serves to promote the resolution of topological problems arising from the circularity of the chromosome by Xer recombination. However, the FtsK checkpoint could be a more general feature of the bacterial cell cycle since FtsK is highly conserved among eubacteria, including species that do not possess a Xer system. Indeed, preliminary results from the lab indicate that DNA transfer by FtsK is required independently of Xer recombination in Vibrio cholerae.
To confirm the existence and the generality of the FtsK checkpoint in bacteria, we will determine the different situations that lead to a requirement for FtsK-mediated DNA transfer by studying chromosome segregation and cell division in V. cholerae. In parallel, we will apply new fluorescent microscopy tools to follow the progression of cell division and chromosome segregation in single live bacterial cells. PALM will notably serve to probe the structure of the FtsK DNA-pumps at a high spatial resolution, FRET will be used to determine their timing of assembly and their interactions with the other cell division proteins, and TIRF will serve to follow in real time their activity with respect to the progression of chromosome dimer resolution, chromosome segregation, and septum closure.
Max ERC Funding
1 565 938 €
Duration
Start date: 2012-02-01, End date: 2017-01-31
Project acronym GEODYCON
Project Geometry and dynamics via contact topology
Researcher (PI) Vincent Maurice Colin
Host Institution (HI) UNIVERSITE DE NANTES
Call Details Starting Grant (StG), PE1, ERC-2011-StG_20101014
Summary I intend to cross ressources of holomorphic curves techniques and traditional topological methods to study some fundamental questions in symplectic and contact geometry such as:
- The Weinstein conjecture in dimension greater than 3.
- The construction of new invariants for both smooth manifolds and Legendrian/contact manifolds, in particular, try to define an analogue of Heegaard Floer homology in dimension larger than 3.
- The link, in dimension 3, between the geometry of the ambient manifold (especially hyperbolicity) and the dynamical/topological properties of its Reeb vector fields and contact structures.
- The topological characterization of odd-dimensional manifolds admitting a contact structure.
A crucial ingredient of my program is to understand the key role played by open book decompositions in dimensions larger than three.
This program requires a huge amount of mathematical knowledges. My idea is to organize a team around Ghiggini, Laudenbach, Rollin, Sandon and myself, augmented by two post-docs and one PhD student funded by the project. This will give us the critical size to organize a very active working seminar and to have a worldwide attractivity and recognition.
I also plan to invite one confirmed researcher every year (for 1-2 months), to organize one conference and one summer school, as well as several focused weeks.
Summary
I intend to cross ressources of holomorphic curves techniques and traditional topological methods to study some fundamental questions in symplectic and contact geometry such as:
- The Weinstein conjecture in dimension greater than 3.
- The construction of new invariants for both smooth manifolds and Legendrian/contact manifolds, in particular, try to define an analogue of Heegaard Floer homology in dimension larger than 3.
- The link, in dimension 3, between the geometry of the ambient manifold (especially hyperbolicity) and the dynamical/topological properties of its Reeb vector fields and contact structures.
- The topological characterization of odd-dimensional manifolds admitting a contact structure.
A crucial ingredient of my program is to understand the key role played by open book decompositions in dimensions larger than three.
This program requires a huge amount of mathematical knowledges. My idea is to organize a team around Ghiggini, Laudenbach, Rollin, Sandon and myself, augmented by two post-docs and one PhD student funded by the project. This will give us the critical size to organize a very active working seminar and to have a worldwide attractivity and recognition.
I also plan to invite one confirmed researcher every year (for 1-2 months), to organize one conference and one summer school, as well as several focused weeks.
Max ERC Funding
887 600 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym GEOPARDI
Project Numerical integration of Geometric Partial Differential Equations
Researcher (PI) Erwan Faou
Host Institution (HI) INSTITUT NATIONAL DE RECHERCHE ENINFORMATIQUE ET AUTOMATIQUE
Call Details Starting Grant (StG), PE1, ERC-2011-StG_20101014
Summary "The goal of this project is to develop new numerical methods for the approximation of evolution equations possessing strong geometric properties such as Hamiltonian systems or stochastic differential equations. In such situations the exact solutions endow with many physical properties that are consequences of the geometric structure: Preservation of the total energy, momentum conservation or existence of ergodic invariant measures. However the preservation of such qualitative properties of the original system by numerical methods at a reasonable cost is not guaranteed at all, even for very precise (high order) methods.
The principal aim of geometric numerical integration is the understanding and analysis of such problems: How (and to which extend) reproduce qualitative behavior of differential equations over long time? The extension of this theory to partial differential equations is a fundamental ongoing challenge, which require the invention of a new mathematical framework bridging the most recent techniques used in the theory of nonlinear PDEs and stochastic ordinary and partial differential equations. The development of new efficient numerical schemes for geometric PDEs has to go together with the most recent progress in analysis (stability phenomena, energy transfers, multiscale problems, etc..)
The major challenges of the project are to derive new schemes by bridging the world of numerical simulation and the analysis community, and to consider deterministic and stochastic equations, with a general aim at deriving hybrid methods. We also aim to create a research platform devoted to extensive numerical simulations of difficult academic PDEs in order to highlight new nonlinear phenomena and test numerical methods."
Summary
"The goal of this project is to develop new numerical methods for the approximation of evolution equations possessing strong geometric properties such as Hamiltonian systems or stochastic differential equations. In such situations the exact solutions endow with many physical properties that are consequences of the geometric structure: Preservation of the total energy, momentum conservation or existence of ergodic invariant measures. However the preservation of such qualitative properties of the original system by numerical methods at a reasonable cost is not guaranteed at all, even for very precise (high order) methods.
The principal aim of geometric numerical integration is the understanding and analysis of such problems: How (and to which extend) reproduce qualitative behavior of differential equations over long time? The extension of this theory to partial differential equations is a fundamental ongoing challenge, which require the invention of a new mathematical framework bridging the most recent techniques used in the theory of nonlinear PDEs and stochastic ordinary and partial differential equations. The development of new efficient numerical schemes for geometric PDEs has to go together with the most recent progress in analysis (stability phenomena, energy transfers, multiscale problems, etc..)
The major challenges of the project are to derive new schemes by bridging the world of numerical simulation and the analysis community, and to consider deterministic and stochastic equations, with a general aim at deriving hybrid methods. We also aim to create a research platform devoted to extensive numerical simulations of difficult academic PDEs in order to highlight new nonlinear phenomena and test numerical methods."
Max ERC Funding
971 772 €
Duration
Start date: 2011-09-01, End date: 2016-08-31
Project acronym GTMT
Project Group Theory and Model Theory
Researcher (PI) Eric Herve Jaligot
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE1, ERC-2011-StG_20101014
Summary The project is located between logic and mathematics, more precisely between model theory and group theory. There are extremely difficult questions arising about the model theory of groups, notably the question of the construction of new groups with prescribed algebraic properties and at the same time good model-theoretic properties. In particular, it is an important question, both in model theory and in group theory, to build new stable groups and eventually new nonalgebraic groups with a good dimension notion.
The present project aims at filling these gaps. It is divided into three main directions. Firstly, it consists in the continuation of the classification of groups with a good dimension notion, notably groups of finite Morley rank or related notions. Secondly, it consists in a systematic inspection of the combinatorial and geometric group theory which can be applied to build new groups, keeping a control on their first order theory. Thirdly, and in connection to the previous difficult problem, it consists in a very systematic and general study of infinite permutation groups.
Summary
The project is located between logic and mathematics, more precisely between model theory and group theory. There are extremely difficult questions arising about the model theory of groups, notably the question of the construction of new groups with prescribed algebraic properties and at the same time good model-theoretic properties. In particular, it is an important question, both in model theory and in group theory, to build new stable groups and eventually new nonalgebraic groups with a good dimension notion.
The present project aims at filling these gaps. It is divided into three main directions. Firstly, it consists in the continuation of the classification of groups with a good dimension notion, notably groups of finite Morley rank or related notions. Secondly, it consists in a systematic inspection of the combinatorial and geometric group theory which can be applied to build new groups, keeping a control on their first order theory. Thirdly, and in connection to the previous difficult problem, it consists in a very systematic and general study of infinite permutation groups.
Max ERC Funding
366 598 €
Duration
Start date: 2011-10-01, End date: 2013-12-31
Project acronym LIC
Project Loop models, integrability and combinatorics
Researcher (PI) Paul Georges Zinn-Justin
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE1, ERC-2011-StG_20101014
Summary The purpose of this proposal is to investigate new connections which
have emerged in the recent years between problems from statistical
mechanics, namely two-dimensional exactly solvable models, and a variety
of combinatorial problems, among which: the enumeration of plane partitions,
alternating sign matrices and related objects;
combinatorial properties of certain
algebro-geometric objects such as orbital varieties or the Brauer loop scheme;
or finally certain problems in free probability. One of the key methods
that emerged in recent years is the use
of quantum integrability and more precisely the quantum Knizhnik--Zamolodchikov
equation, which itself is related to many deep results in representation theory.
The fruitful interaction between all these ideas has led to many advances
in the last few years, including proofs of some old conjectures but
also completely new results. More specifically, loop models
are a class of statistical models where the PI has made
significant progress, in particular in relation to the so-called
Razumov--Stroganov conjecture (now Cantini--Sportiello theorem).
New directions that should be pursued include:
further applications to enumerative combinatorics such as proofs of various
open conjectures relating Alternating Sign Matrices, Plane Partitions
and their symmetry classes;
a full understanding of the quantum integrability of the
Fully Packed Loop model,
a specific loop model at the heart of the Razumov--Stroganov correspondence;
a complete description of the Brauer loop scheme, including its
defining equations, and of the underlying poset; the extension
of the work on Di Francesco and Zinn-Justin on the loop model/6-vertex vertex
relation to the case of the 8-vertex model
(corresponding to elliptic solutions of the Yang--Baxter equation);
the study of solvable tilings models, in relation to
generalizations of the Littlewood--Richardson rule, and the determination
of their limiting shapes.
Summary
The purpose of this proposal is to investigate new connections which
have emerged in the recent years between problems from statistical
mechanics, namely two-dimensional exactly solvable models, and a variety
of combinatorial problems, among which: the enumeration of plane partitions,
alternating sign matrices and related objects;
combinatorial properties of certain
algebro-geometric objects such as orbital varieties or the Brauer loop scheme;
or finally certain problems in free probability. One of the key methods
that emerged in recent years is the use
of quantum integrability and more precisely the quantum Knizhnik--Zamolodchikov
equation, which itself is related to many deep results in representation theory.
The fruitful interaction between all these ideas has led to many advances
in the last few years, including proofs of some old conjectures but
also completely new results. More specifically, loop models
are a class of statistical models where the PI has made
significant progress, in particular in relation to the so-called
Razumov--Stroganov conjecture (now Cantini--Sportiello theorem).
New directions that should be pursued include:
further applications to enumerative combinatorics such as proofs of various
open conjectures relating Alternating Sign Matrices, Plane Partitions
and their symmetry classes;
a full understanding of the quantum integrability of the
Fully Packed Loop model,
a specific loop model at the heart of the Razumov--Stroganov correspondence;
a complete description of the Brauer loop scheme, including its
defining equations, and of the underlying poset; the extension
of the work on Di Francesco and Zinn-Justin on the loop model/6-vertex vertex
relation to the case of the 8-vertex model
(corresponding to elliptic solutions of the Yang--Baxter equation);
the study of solvable tilings models, in relation to
generalizations of the Littlewood--Richardson rule, and the determination
of their limiting shapes.
Max ERC Funding
840 120 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym MOLSTRUCTTRANSFO
Project Molecular and Structural Biology of Bacterial Transformation
Researcher (PI) Rémi Fronzes
Host Institution (HI) INSTITUT PASTEUR
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary A common form of gene transfer is the vertical gene transfer between one organism and its offspring during sexual reproduction. However, some organisms, such as bacteria, are able to acquire genetic material independently of sexual reproduction by horizontal gene transfer (HGT). Three mechanisms mediate HGT in bacteria: conjugation, transduction and natural transformation. HGT and the selective pressure exerted by the widespread use antibiotics (in medicine, veterinary medicine, agriculture, animal feeding, etc) are responsible for the rapid spread of antibiotic resistance genes among pathogenic bacteria.
In this proposal, we focus on bacterial transformation systems, also named competence systems. Natural transformation is the acquisition of naked DNA from the extracellular milieu. It is the only programmed process for generalized genetic exchange found in bacteria. This highly efficient and regulated process promotes bacterial genome plasticity and adaptive response of bacteria to changes in their environment. It is essential for bacterial survival and/or virulence and greatly limits efficiency of treatments or vaccine against some pathogenic bacteria.
The architecture and functioning of the membrane protein complexes mediating DNA transfer through the cell envelope during bacterial transformation remain elusive. We want to decipher the molecular mechanism of this transfer. To attain this goal, we will carry out structural biology studies (X-ray crystallography and high resolution electron microscopy) as well as functional and structure-function in vivo studies. We have the ambition to make major contributions to the understanding of bacterial transformation. Ultimately, we hope that our results will also help to find compounds that could block natural transformation in bacterial pathogens.
Summary
A common form of gene transfer is the vertical gene transfer between one organism and its offspring during sexual reproduction. However, some organisms, such as bacteria, are able to acquire genetic material independently of sexual reproduction by horizontal gene transfer (HGT). Three mechanisms mediate HGT in bacteria: conjugation, transduction and natural transformation. HGT and the selective pressure exerted by the widespread use antibiotics (in medicine, veterinary medicine, agriculture, animal feeding, etc) are responsible for the rapid spread of antibiotic resistance genes among pathogenic bacteria.
In this proposal, we focus on bacterial transformation systems, also named competence systems. Natural transformation is the acquisition of naked DNA from the extracellular milieu. It is the only programmed process for generalized genetic exchange found in bacteria. This highly efficient and regulated process promotes bacterial genome plasticity and adaptive response of bacteria to changes in their environment. It is essential for bacterial survival and/or virulence and greatly limits efficiency of treatments or vaccine against some pathogenic bacteria.
The architecture and functioning of the membrane protein complexes mediating DNA transfer through the cell envelope during bacterial transformation remain elusive. We want to decipher the molecular mechanism of this transfer. To attain this goal, we will carry out structural biology studies (X-ray crystallography and high resolution electron microscopy) as well as functional and structure-function in vivo studies. We have the ambition to make major contributions to the understanding of bacterial transformation. Ultimately, we hope that our results will also help to find compounds that could block natural transformation in bacterial pathogens.
Max ERC Funding
1 405 149 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym MOMP
Project Structural Biology of Mitochondrial Outer Membrane Proteins
Researcher (PI) Sebastian Hiller Odermatt
Host Institution (HI) UNIVERSITAT BASEL
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary To elucidate the biological role of the mitochondrial outer membrane (MOM), I propose to determine structures and functions of integral MOM protein complexes at atomic resolution, involving the three proteins VDAC, Bax and Sam. These are key elements of vital cellular functions: the regulation of bioenergetics, mitochondrial biogenesis, apoptosis and cancer. Our results will give new insights into the biology of eukaryotes and will open up new avenues for pharmaceutical applications.
My research group will pursue the following objectives:
A. Determination of the structures of the VDAC–NADH, the VDAC–cholesterol, and the VDAC–hexokinase complexes. These structures will provide the molecular basis for metabolism regulation by the voltage-dependent anion channel VDAC and for its role in the “Warburg effect”, a crucial step of cancerogenesis of most cancers.
B. Determination of the structure and insertion mechanism of the Bax transmembrane-pore and its formation and inhibition by drug candidates. The formation of the Bax pore in the MOM is the final, deadly step in mitochondrial apoptosis and the structure will thus elucidate a key regulatory element of multicellular organisms.
C. Determination of the structure and function of the sorting and assembly machinery (Sam), including its core protein, the beta-barrel protein Sam50, and its interactions with substrates. These results will explain the insertion of membrane proteins during the biogenesis of the MOM, an essential for eukaryotic life.
Structure determinations of membrane proteins are still major technical challenges and so far, with VDAC, only a single structure of an integral MOM protein is known, determined by the present author and colleagues. While bringing groundbreaking biological insights, our research will further extend the methodological approaches for membrane protein structure determination by nuclear magnetic resonance (NMR) spectroscopy to a new level.
Summary
To elucidate the biological role of the mitochondrial outer membrane (MOM), I propose to determine structures and functions of integral MOM protein complexes at atomic resolution, involving the three proteins VDAC, Bax and Sam. These are key elements of vital cellular functions: the regulation of bioenergetics, mitochondrial biogenesis, apoptosis and cancer. Our results will give new insights into the biology of eukaryotes and will open up new avenues for pharmaceutical applications.
My research group will pursue the following objectives:
A. Determination of the structures of the VDAC–NADH, the VDAC–cholesterol, and the VDAC–hexokinase complexes. These structures will provide the molecular basis for metabolism regulation by the voltage-dependent anion channel VDAC and for its role in the “Warburg effect”, a crucial step of cancerogenesis of most cancers.
B. Determination of the structure and insertion mechanism of the Bax transmembrane-pore and its formation and inhibition by drug candidates. The formation of the Bax pore in the MOM is the final, deadly step in mitochondrial apoptosis and the structure will thus elucidate a key regulatory element of multicellular organisms.
C. Determination of the structure and function of the sorting and assembly machinery (Sam), including its core protein, the beta-barrel protein Sam50, and its interactions with substrates. These results will explain the insertion of membrane proteins during the biogenesis of the MOM, an essential for eukaryotic life.
Structure determinations of membrane proteins are still major technical challenges and so far, with VDAC, only a single structure of an integral MOM protein is known, determined by the present author and colleagues. While bringing groundbreaking biological insights, our research will further extend the methodological approaches for membrane protein structure determination by nuclear magnetic resonance (NMR) spectroscopy to a new level.
Max ERC Funding
1 997 190 €
Duration
Start date: 2011-12-01, End date: 2016-11-30
Project acronym NDOGS
Project Nuclear Dynamic, Organization and Genome Stability
Researcher (PI) Karine Marie Renée Dubrana
Host Institution (HI) COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary The eukaryotic genome is packaged into large-scale chromatin structures occupying distinct domains in the cell nucleus. Nuclear compartmentalization has recently been proposed to play an important role in genome stability but the molecular steps regulated remain to be defined. Focusing on Double strand breaks (DSBs) in response to which cells activate checkpoint and DNA repair pathways, we propose to characterize the spatial and temporal behavior of damaged chromatin and determine how this affects the maintenance of genome integrity. Currently, most studies concerning DSBs signaling and repair have been realized on asynchronous cell populations, which makes it difficult to precisely define the kinetics of events that occur at the cellular level. We thus propose to follow the nuclear localization and dynamics of an inducible DSB concomitantly with the kinetics of checkpoint activation and DNA repair at a single cell level and along the cell cycle. This will be performed using budding yeast as a model system enabling the combination of genetics, molecular biology and advanced live microscopy. We recently demonstrated that DSBs relocated to the nuclear periphery where they contact nuclear pores. This change in localization possibly regulates the choice of the repair pathway through steps that are controlled by post-translational modifications. This proposal aims at dissecting the molecular pathways defining the position of DSBs in the nucleus by performing genetic and proteomic screens, testing the functional consequence of nuclear position for checkpoint activation and DNA repair by driving the DSB to specific nuclear landmarks and, defining the dynamics of DNA damages in different repair contexts. Our project will identify new players in the DNA repair and checkpoint pathways and further our understanding of how the compartmentalization of damaged chromatin into the nucleus regulates these processes to insure the transmission of a stable genome.
Summary
The eukaryotic genome is packaged into large-scale chromatin structures occupying distinct domains in the cell nucleus. Nuclear compartmentalization has recently been proposed to play an important role in genome stability but the molecular steps regulated remain to be defined. Focusing on Double strand breaks (DSBs) in response to which cells activate checkpoint and DNA repair pathways, we propose to characterize the spatial and temporal behavior of damaged chromatin and determine how this affects the maintenance of genome integrity. Currently, most studies concerning DSBs signaling and repair have been realized on asynchronous cell populations, which makes it difficult to precisely define the kinetics of events that occur at the cellular level. We thus propose to follow the nuclear localization and dynamics of an inducible DSB concomitantly with the kinetics of checkpoint activation and DNA repair at a single cell level and along the cell cycle. This will be performed using budding yeast as a model system enabling the combination of genetics, molecular biology and advanced live microscopy. We recently demonstrated that DSBs relocated to the nuclear periphery where they contact nuclear pores. This change in localization possibly regulates the choice of the repair pathway through steps that are controlled by post-translational modifications. This proposal aims at dissecting the molecular pathways defining the position of DSBs in the nucleus by performing genetic and proteomic screens, testing the functional consequence of nuclear position for checkpoint activation and DNA repair by driving the DSB to specific nuclear landmarks and, defining the dynamics of DNA damages in different repair contexts. Our project will identify new players in the DNA repair and checkpoint pathways and further our understanding of how the compartmentalization of damaged chromatin into the nucleus regulates these processes to insure the transmission of a stable genome.
Max ERC Funding
1 499 863 €
Duration
Start date: 2012-02-01, End date: 2018-01-31
