ERC FUNDED PROJECTS

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown. Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps. This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

1 999 750 €

Start date: 2017-03-01, End date: 2022-02-28

The goal of this project is to develop a mathematical theory for steady three-dimensional water waves with vorticity. The mathematical model consists of the incompressible Euler equations with a free surface, and vorticity is important for modelling the interaction of surface waves with non-uniform currents. In the two-dimensional case, there has been a lot of progress on water waves with vorticity in the last decade. This progress has mainly been based on the stream function formulation, in which the problem is reformulated as a nonlinear elliptic free boundary problem. An analogue of this formulation is not available in three dimensions, and the theory has therefore so far been restricted to irrotational flow. In this project we seek to go beyond this restriction using two different approaches. In the first approach we will adapt methods which have been used to construct three-dimensional ideal flows with vorticity in domains with a fixed boundary to the free boundary context (for example Beltrami flows). In the second approach we will develop methods which are new even in the case of a fixed boundary, by performing a detailed study of the structure of the equations close to a given shear flow using ideas from infinite-dimensional bifurcation theory. This involves handling infinitely many resonances.

1 203 627 €

Start date: 2016-03-01, End date: 2022-02-28

Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.

1 499 375 €

Start date: 2016-07-01, End date: 2021-06-30

Compound semiconductor solar cells are providing the highest photovoltaic conversion efficiency, yet their performance lacks far behind the theoretical potential. This is a position we will challenge by engineering advanced III-V optoelectronics materials and heterostructures for better utilization of the solar spectrum, enabling efficiencies approaching practical limits. The work is strongly motivated by the global need for renewable energy sources. To this end, AMETIST framework is based on three vectors of excellence in: i) material science and epitaxial processes, ii) advanced solar cells exploiting nanophotonics concepts, and iii) new device fabrication technologies. Novel heterostructures (e.g. GaInNAsSb, GaNAsBi), providing absorption in a broad spectral range from 0.7 eV to 1.4 eV, will be synthesized and monolithically integrated in tandem cells with up to 8-junctions. Nanophotonic methods for light-trapping, spectral and spatial control of solar radiation will be developed to further enhance the absorption. To ensure a high long-term impact, the project will validate the use of state-of-the-art molecular-beam-epitaxy processes for fabrication of economically viable ultra-high efficiency solar cells. The ultimate efficiency target is to reach a level of 55%. This would enable to generate renewable/ecological/sustainable energy at a levelized production cost below ~7 ¢/kWh, comparable or cheaper than fossil fuels. The work will also bring a new breath of developments for more efficient space photovoltaic systems. AMETIST will leverage the leading position of the applicant in topical technology areas relevant for the project (i.e. epitaxy of III-N/Bi-V alloys and key achievements concerning GaInNAsSb-based tandem solar cells). Thus it renders a unique opportunity to capitalize on the group expertize and position Europe at the forefront in the global competition for demonstrating more efficient and economically viable photovoltaic technologies.

2 492 719 €

Start date: 2017-01-01, End date: 2021-12-31