ERC FUNDED PROJECTS

DNA repair pathways evolved as an intricate network that senses DNA damage and resolves it in order to minimise genetic lesions and thus preventing tumour formation. Gaining in recognition the last few years, the alternative end-joining (alt-EJ) DNA repair pathway was recently shown to be up-regulated and required for cancer cell viability in the absence of homologous recombination-mediated repair (HR). Despite this integral role, the alt-EJ repair pathway remains poorly characterised in humans. As such, its molecular composition, regulation and crosstalk with HR and other repair pathways remain elusive. Additionally, the contribution of the alt-EJ pathway to tumour progression as well as the identification of a mutational signature associated with the use of alt-EJ has not yet been investigated. Moreover, the clinical relevance of developing small-molecule inhibitors targeting players in the alt-EJ pathway, such as the polymerase Pol Theta (Polθ), is of importance as current anticancer drug treatments have shown limited effectiveness in achieving cancer remission in patients with HR-deficient (HRD) tumours. Here, we propose a novel, multidisciplinary approach that aims to characterise the players and mechanisms of action involved in the utilisation of alt-EJ in cancer. This understanding will better elucidate the changing interplay between different DNA repair pathways, thus shedding light on whether and how the use of alt-EJ contributes to the pathogenic history and survival of HRD tumours, eventually paving the way for the development of novel anticancer therapeutics. For all the abovementioned reasons, we are convinced this project will have important implications in: 1) elucidating critical interconnections between DNA repair pathways, 2) improving the basic understanding of the composition, regulation and function of the alt-EJ pathway, and 3) facilitating the development of new synthetic lethality-based chemotherapeutics for the treatment of HRD tumours.

1 498 750 €

Start date: 2017-07-01, End date: 2022-06-30

The overall goal of this project is to develop new concepts and techniques in geometric and asymptotic group theory for a systematic study of the analytic properties of discrete groups. These are properties depending on the unitary representation theory of the group. The fundamental examples are amenability, discovered by von Neumann in 1929, and property (T), introduced by Kazhdan in 1967. My main objective is to establish the precise relations between groups recently appeared in K-theory and topology such as C*-exact groups and groups coarsely embeddable into a Hilbert space, versus those discovered in ergodic theory and operator algebra, for example, sofic and hyperlinear groups. This is a first ever attempt to confront the analytic behavior of so different nature. I plan to work on crucial open questions: Is every coarsely embeddable group C*-exact? Is every group sofic? Is every hyperlinear group sofic? My motivation is two-fold: - Many outstanding conjectures were recently solved for these groups, e.g. the Novikov conjecture (1965) for coarsely embeddable groups by Yu in 2000 and the Gottschalk surjunctivity conjecture (1973) for sofic groups by Gromov in 1999. However, their group-theoretical structure remains mysterious. - In recent years, geometric group theory has undergone significant changes, mainly due to the growing impact of this theory on other branches of mathematics. However, the interplay between geometric, asymptotic, and analytic group properties has not yet been fully understood. The main innovative contribution of this proposal lies in the interaction between 3 axes: (i) limits of groups, in the space of marked groups or metric ultralimits; (ii) analytic properties of groups with curvature, of lacunary or relatively hyperbolic groups; (iii) random groups, in a topological or statistical meaning. As a result, I will describe the above apparently unrelated classes of groups in a unified way and will detail their algebraic behavior.

1 065 500 €

Start date: 2011-04-01, End date: 2016-03-31

Autophagy is a catabolic pathway that delivers cytoplasmic material to lysosomes for degradation. Under vegetative conditions, the pathway serves as quality control system, specifically targeting damaged or superfluous organelles and protein-aggregates. Cytotoxic stresses and starvation, however, induces the formation of larger autophagosomes that capture cargo unselectively. Autophagosomes are being generated from a cup-shaped precursor membrane, the isolation membrane, which expands to engulf cytoplasmic components. Sealing of this structure gives rise to the double-membrane surrounded autophagosomes. Two interconnected ubiquitin (Ub)-like conjugation systems coordinate the expansion of autophagosomes by conjugating the autophagy related (Atg)-protein Atg8 to the isolation membrane. In an effort to unravel the function of Atg8, we reconstituted the system on model membranes in vitro and found that Atg8 forms together with the Atg12–Atg5-Atg16 complex a membrane scaffold which is required for productive autophagy in yeast. Humans possess seven Atg8-homologs and two mutually exclusive Atg16-variants. Here, we propose to investigate the function of the human Ub-like conjugation system using a fully reconstituted in vitro system. The spatiotemporal organization of recombinant fluorescent-labeled proteins with synthetic model membranes will be investigated using confocal and TIRF-microscopy. Structural information will be obtained by atomic force and electron microscopy. Mechanistic insights, obtained from the in vitro work, will be tested in vivo in cultured human cells. We belief that revealing 1) the function of the human Ub-like conjugation system in autophagy, 2) the functional differences of Atg8-homologs and the two Atg16-variants Atg16L1 and TECPR1 and 3) how Atg16L1 coordinates non-canonical autophagy will provide essential insights into the pathophysiology of cancer, neurodegenerative, and autoimmune diseases.

1 499 726 €

Start date: 2015-04-01, End date: 2020-03-31

Boundary layer theory is a large component of fluid dynamics. It is ubiquitous in Oceanography, where boundary layer currents, such as the Gulf Stream, play an important role in the global circulation. Comprehending the underlying mechanisms in the formation of boundary layers is therefore crucial for applications. However, the treatment of boundary layers in ocean dynamics remains poorly understood at a theoretical level, due to the variety and complexity of the forces at stake. The goal of this project is to develop several tools to bridge the gap between the mathematical state of the art and the physical reality of oceanic motion. There are four points on which we will mainly focus: degeneracy issues, including the treatment Stewartson boundary layers near the equator; rough boundaries (meaning boundaries with small amplitude and high frequency variations); the inclusion of the advection term in the construction of stationary boundary layers; and the linear and nonlinear stability of the boundary layers. We will address separately Ekman layers and western boundary layers, since they are ruled by equations whose mathematical behaviour is very different. This project will allow us to have a better understanding of small scale phenomena in fluid mechanics, and in particular of the inviscid limit of incompressible fluids. The team will be composed of the PI, two PhD students and three two-year postdocs over the whole period. We will also rely on the historical expertise of the host institution on fluid mechanics and asymptotic methods.

1 267 500 €

Start date: 2015-09-01, End date: 2020-08-31