Investigating the essential roles of Ubiquitin-like molecules and the Ubiquitin Proteasome System
2003: PhD in Biology and Health, University of Sciences of Montpellier, France
SUMO in the control of gene expression in physiological and pathological conditions
SUMO is a family of peptidic post-translational modifier related to Ubiquitin that are covalently and reversibly conjugated to thousands of proteins. SUMOylation plays a role as important as phosphorylation in the control of various cellular processes. In particular, one of the main functions of SUMOylation is the control of gene expression.
Our group has been focusing on the SUMOylation of AP-1 transcription factors, in particular c-Fos and c-Jun, which play key roles in the control of numerous physiological and pathological pathways. We identified their SUMOylated lysines and showed that their SUMOylation limit their activity (Bossis et al, Mol Cell Biol, 2005). More recently, thanks to the generation of an antibody specific for the SUMOylated form of c-Fos, the first of its kind, we could demonstrate that c-Fos SUMOylation occurs on its target promoters during transcriptional activation to limit the extent of target gene activation and maintain them within physiological windows (Tempé et al, Oncogene, 2014).
Another aspect of our work concerns the role of SUMOylation in the regulation of gene expression in a pathological situation: Acute Myeloid Leukemias (AML) response to chemotherapeutic drugs. AML are severe hematological malignancies, whose treatment has not significantly changer over the past 40 years. The relapse rates after induction therapy (anthracycline and nucleoside analogue) are high and, at relapse, patients become refractory to the treatments, which explains the poor prognosis of this disease. We have shown that treatment of AML cells (cell lines, patient samples and mouse models) induce a deSUMOylation of cellular proteins that starts before the induction of apoptosis. This deSUMOylation is due to the inactivation of the SUMO E1 and E2 enzymes by ROS (Reactive Oxygen Species) produced by genotoxics owing to a mechanism we discovered (Bossis and Melchior, Mol Cell, 2006), that involves the formation of a disulphide bond between their catalytic cysteines. This genotoxics-induced deSUMOylation is involved in the activation of specific genes and participates in the induction of apoptosis. In addition, we could show that targeting this ROS/SUMO axis could be a way to overcome AML chemoresistance (Bossis et al, Cell Reports, 2014). This project is carried out in close collaboration with the team of Jean-Emmanuel Sarry and Christian Récher (CRCT, Toulouse) and with Yosr Hichri and Guillaume Cartron at the Clinical Hematology department of the Montpellier University. Our current work aims at (i) understanding at a global scale how the ROS/SUMO axis controls specific gene programs using both transcriptomic, genomic (ChIP-Seq) and proteomic (SILAC) approaches and (ii) determining the prognosis and therapeutical potential of the ROS/SUMO axis in AML treatment.
Keywords: SUMO, Fos, Jun, AP-1, ubiquitin/proteasome, cell signalling, transcriptome, large-scale genomic studies, redox metabolism, leukemia, chemotherapy
1- Bossis, G.*, Sarry, JE., Kifagi, C., Ristic, M., Salland, E., Vergez, F., Salem, T., Boutzen, H., Baik, H., Brockly, F., Pelegrin, M., Recher, C., Manenti, S. and Piechaczyk, M*. (2014) The ROS/SUMO axis contributes to the response of human Acute Myeloid Leukemia to chemotherapeutic drugs. (2014) Cell Reports. 7 (6): 1815-1823 * co-corresponding authors
2- Tempe,D., Vives,E., Brockly,F., Brooks,H., De Rossi,S., Piechaczyk,M. and Bossis,G. (2014) SUMOylation of the inducible (c-Fos:c-Jun)/AP-1 transcription complex occurs on target promoters to limit transcriptional activation. Oncogene, 33 (7):921-927
3- Bonne-Andrea,C., Kahli,M., Mechali,F., Lemaitre,J.-M., Bossis,G. and Coux,O. (2013) SUMO2/3 modification of cyclin E contributes to the control of replication origin firing. Nat. Commun., 4, 1850.
4- Schreiner S, Martinez R, Groitl P, Rayne F, Vaillant R, Wimmer P, Bossis G, Sternsdorf T, Marcinowski L, Ruzsics Z, Dobner T, Wodrich H (2012) Transcriptional Activation of the Adenoviral Genome Is Mediated by Capsid Protein VI. PLoS Pathog 8(2): e1002549.
5- Krumova P, Meulmeester E, Garrido M, Tirard M, Hsiao HH, Bossis G, Urlaub H, Zweckstetter M, Kügler S, Melchior F, Bähr M, Weishaupt JH (2011) Sumoylation inhibits alpha-synuclein aggregation and toxicity. J Cell Biol. 194(1):49-60.
6- Talotta F, Mega T, Bossis G, Casalino L, Basbous J, Jariel-Encontre I, Piechaczyk M, Verde P (2010). Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. Oncogene. 29(33):4732-40
7- Tempe, D., Piechaczyk, M., and Bossis, G. (2008). SUMO under stress. Biochem Soc Trans 36, 874-878.
8- Le Cam, L., Linares, L. K., Paul, C., Julien, E., Lacroix, M., Hatchi, E., Triboulet, R., Bossis, G., Shmueli, A., Rodriguez, M. S., et al. (2006). E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell 127, 775-788.
9- Bossis, G., and Melchior, F. (2006). Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol Cell 21, 349-357.
10- Bossis, G., Malnou, C. E., Farras, R., Andermarcher, E., Hipskind, R., Rodriguez, M., Schmidt, D., Muller, S., Jariel-Encontre, I., and Piechaczyk, M. (2005). Down-regulation of c- Fos/c-Jun AP-1 dimer activity by sumoylation. Mol Cell Biol 25, 6964-6979.