In eukaryotes, SUMO (Small Ubiquitin Modifier) conjugation to proteins is an essential process that regulates many aspects of cell biology. Defects in SUMO conjugation have been associated to cancer, neurodegenerative diseases and others, raising a great interest in developing novel drugs for inhibiting SUMO conjugation. Specifically, recent reports have pointed to a high dependency on an active SUMO conjugation by Myc-overexpressing cancers. Consequently, SUMO conjugation has become a non-oncogene addiction target of special relevance since the oncogenic Myc is nondruggable. Based on the results obtained by our group, we have developed a novel assay for identifying efficient SUMO conjugation inhibitors, which could lead to the identification of novel therapeutic drugs. The main outcome that we expect to obtain from this project is the identification of a SUMOylation inhibitor that will be patent protected. Initial steps towards the valorization of the identified product will be taken, and available commercialization opportunities will be carefully analyzed for entering into the next steps of drug development, including preclinical and clinical studies. The fact that SUMOylation may be a key element in almost 70% of cancer types due to its involvement in the Myc pathway makes the search for hit drug candidates an enterprise worth taking, which could benefit millions of people worldwide.

Tomato is one of the most economically relevant crops in the world and is the main model system for fruit ripening studies at biochemical, genetic and molecular levels. In this climacteric fruit, a sudden increase in respiration takes place at the onset of ripening, usually in concert with increased production of ethylene that eventually impacts fruit color, firmness, taste, and flavor. During ripening, tomato accumulates high contents of health-promoting carotenoids (pro-vitamin A, antioxidants), which require a high production of carbon precursors and ATP. In this respect, both mitochondrial and chromoplast respiration have been proposed to play important roles in fruit ripening and carotenoid metabolism. The general aim of this project is to determine the contribution of mitochondrial respiration to the supply of energy and carbon for the production of carotenoids in tomato fruit during ripening. In particular, we will perform metabolomics of genetically modified tomatoes with altered mitochondrial and chromoplast respiration at different ripening stages. Furthermore, 13C- and 14C-labelling experiments will be performed to trace the fate of carbon from primary to secondary metabolites. In parallel, we will measure the relative glycolytic and TCA cycle fluxes and, for the first time in tomato, the in vivo activities of mitochondrial electron transport chain pathways by using the 18O fractionation technique. Combining these data with the analysis of transcript and protein levels of the main components of respiratory and carotenoid pathways and mathematical modelling will unveil novel metabolic checkpoints and connections between primary and secondary metabolism during fruit ripening. The generated new insights should contribute to the implementation of new biotechnological approaches to produce fruits with enhanced levels of carotenoids and other health-promoting secondary metabolites.

Environmental stressors such as nutritional imbalances, severe temperature, drought, and salinity are detrimental to plant growth. As a major strategy for adaptation to environmental stressors, plants have evolved extracellular barriers as part of their cell walls made of aliphatic biopolymers, cutin and suberin, along with their associated waxes. Cutin and cuticular waxes form the cuticle that covers the outer surfaces of leaves, fruits, and flowers. Suberin, on the other hand, is present in the extracellular space of inner tissues, such as endodermis, periderm, and exodermis, as well as the seed coat. Both cutin and suberin act as barriers, preventing water loss and nutrient leakage while also shielding the plant from pathogens. Despite decades of studies on these biopolymers, many essential aspects of their biosynthesis and assembly remain unclear. Among these is our understanding of the assembly of cuticle and suberin monomers in the extracellular space, as well as the control of the polymerising machinery both developmentally and environmentally. A few members of the GDSL-esterases/lipases (GELP) family have been shown to be involved in the polymerisation of tomato fruit cuticle and Arabidopsis thaliana root suberin. Intriguingly, another subset of GELPs has been shown to be able to degrade cutin or suberin, implying a complex mechanism that plants have evolved to modulate the dynamics of these polymers. On a regulatory level, several MYB transcription factors have been shown to be important in controlling the developmental and tissue-specific responses of suberin and cutin. The proposed research aims at uncovering the mechanisms of MYB-directed and GELP-mediated cuticle and suberin assembly and plasticity during growth and adaptation. Importantly, as part of our proposed work, we intend to use MYBs to manipulate suberin and cutin deposition at the tissue level to create new crop resilience strategies to environmental stressors including drought and salinity.