Ubiquitination in genetic diseases (Prof. Meroni)

Research Strand:

Prof. Germana Meroni

Tel: +39 040 558 8679
Tel: +39 040 375 7718
email: gmeroni@units.it

Biosketch

Germana Meroni is Associate Professor of Genetics at the University of Trieste since February 2015.

Germana Meroni graduated in Biological Sciences at the University of Milan. She had her research training at the University of Milan and at DiBIT-San Raffaele Hospital in Milan before moving as post-doctoral fellow at the Department of Human Genetics at Baylor College of Medicine, Houston, TX (USA). From 1995 to 2000 she was Staff Researcher at the Telethon Institute of Genetics and Medicine (TIGEM) in Milan and in 2000 she established her independent group at TIGEM in Naples where she worked until June 2009. She has been group leader at the Cluster in Biomedicine (CBM) in AREA Science Park in Trieste from July 2009 to January 2015.

Germana Meroni’s research interests focus on the study of the Tripartite Motif (TRIM) family of E3 ubiquitin ligases in health and in genetic diseases. Her main contribution in the field include: the initial definition and characterization of this family (Reymond A*, Meroni G*, EMBO J 2001); the identification of MID1/TRIM18, responsible for Opitz Syndrome, as an actor in cytoskeletal regulation (Cainarca, Hum Mol Gen 1999; Berti, BMC Cell Biol 2004) and in cerebellar development (Lancioni, J Neuroscience 2010); the characterization of TRIM E3 ligases interaction with selected ubiquitin conjugating enzymes within their E3 ligases function (Napolitano, Biochemical J. 2011; Napolitano, IUBMB Life 2012; Lazzari, Cells 2019); being one of the international reference laboratories for Opitz Syndrome collecting and screening over 300 patients’ sample for molecular diagnosis (Fontanella, Hum Mutation 2008; Migliore, EJMG 2013).

Info

Research

The TRIM family is the largest RING-type class of Ubiquitin E3 ligases counting in mammals more than 70 members that are characterized by the presence of the Tripartite Motif composed of a RING domain, one or two B-box domains, and a Coiled-coil region. TRIM proteins are involved in a plethora of important cellular processes and their alterations result in clinically relevant conditions, such as inherited disorders, cancer, and innate pathogen response.

The overall objective of our research is to unravel the function of the TRIM gene family to understand TRIM’s activity basic mechanisms as well as their patho-physiological implications in genetic disorders.

CURRENT PROJECTS

1) The TRIM family as the largest RING-type class of Ubiquitin E3 ligases

The E3 activity for several TRIM proteins has been assessed, although, in many instances the specific interaction with the ubiquitylation machinery is still unclear. During the ubiquitylation process, target protein specificity is provided by the E3, whereas the E2 and E3 combination determines the topology and length of the ubiquitin chains to be conjugated to the substrate. Together with specificity, this is one of the most important features of the ubiquitylation process as it determines the fate of the modified substrate. We are interested in studying: TRIM-E2 binding specificity definition; TRIM-E2 pairs in ubiquitylation; and TRIM homo- and hetero-interactions in ubiquitylation.

2) The MID1/TRIM18 gene in the pathogenesis of Opitz Syndrome

Opitz Syndrome (OS) is an X-linked congenital anomaly disorder characterized by midline developmental defects. The gene mutated in OS is MID1/TRIM18 and encodes an E3 ligase associated with the microtubular apparatus throughout the cell cycle. The goal of this project is to unravel the pathogenetic causes of OS by exploiting a mouse model we have generated and through an extensive cellular/molecular characterization of the MID1/TRIM18 protein product. In particular we are interested in: i) Unravelling the molecular and developmental events triggered by the lack of Mid1 in the cerebellum as the mouse model recapitulating the neurological signs of the disease results in defective development of the anterior lobes of the cerebellar vermis; ii) Understand MID1/TRIM-mediated regulation of cytoskeletal dynamics through the control of several known and novel substrates.

3) Study of TRIM32, the ubiquitin ligase mutated in Limb Girdle Muscular Dystrophy 2H

Mutations in the TRIM32 gene are implicated in Limb-Girdle-Muscular-Dystrophy 2H. In addition, TRIM32 is also mutated in a different genetic disease, Bardet-Biedl type 11 but it is also implicated in tumorigenesis. Given the identification of several TRIM32 substrates and the pleiotropic involvement of TRIM32 in quite diverse processes, we aim at dissecting the ability to form different TRIM32-E2 ligase complexes and to catalysis different ubiquitin chain modifications in relation to the nature of the substrate.

The overall objective of this project is to understand if distinct TRIM32-E2 complexes occur, how they are organized and spatially arranged, and which outcome they determine on TRIM32 substrates through the integration of biochemical, cellular and structural approaches. Understanding the biochemistry underpinning TRIM32 activity is crucial to determine the fate of the ubiquitinated targets and is a critical step to unravel TRIM32 role within physiological and pathological processes and, in the long-term, towards a proper design of therapeutic intervention.

4) H2020 MSCA-ITN 2018 TRIM-NET Training network in drug discovery targeting TRIM ubiquitin ligases in disease

The project “TRIM-NET: Training network in drug discovery targeting TRIM ubiquitin ligases in disease” funded by the European Union Horizon 2020 Marie Sklodowska-Curie Innovative Training Network programme started in 2019 January 1st.

TRIM-NET is a 4-year-project funded with a total budget of 3,2 M€. It aims at addressing TRIM ubiquitin ligase activity and regulation to develop novel therapeutics for the treatment of different types of cancer, rare genetic neuromuscular disorders, and neurodegenerative diseases.

The project is coordinated by Germana Meroni of the Department of Life Sciences, University of Trieste and includes 9 academic partners from the United Kingdom, Spain, Germany, France, Germany and Netherlands, plus 5 non-academic Partner Organisations. The TRIM-NET consortium is designed to bring together a multidisciplinary team, which connects different expertise (genetics, biochemistry, molecular and cell biology, chemical biology, structural biology) across Europe. Marie Skłodowska-Curie ITN actions aim to promote training and international mobility for early stage researchers. The group of G. Meroni recruited 2 PhD students within this European project.

People

Current Group Members

Elisa Lazzari, Post-doctoral fellow

Martina Mascaro, PhD student

Lu (Shaw) Xiong, PhD student

Inês Fernandes Lages, PhD student

Alumni

Silvia Cainarca (Axxam S.p.A., Milan, Italy)

Silvia Messali (Nerviano Medical Sciences)

Rosa Ferrentino (Institute of Genetics and Biophysics – IGB – Naples)

Caterina Berti (New York University, NY, USA)

Bianca Fontanella (Telethon Institute of Genetics and Medicine – TIGEM – Pozzuoli, NA)

Stefano Cairo (Xentech, Paris, France)

Mariateresa Pizzo (Telethon Institute of Genetics and Medicine – TIGEM – Pozzuoli, NA)

Francesca De Falco (IRCCS–Fondazione SDN, Naples)

Danilo Maddalo (Novartis, Basel, CH)

Valeria Perrina (Institute of Pathology University Hospital Basel, CH)

Angelo Raggioli (EMBL, Monterotondo)

Alessio Lancioni

Luisa Napolitano (SISSA, Trieste, Italy)

Milos Busarcevic (United World College, Duino, Trieste, Italy)

Medhat El-Halawany (University of Cairo, Giza, Egypt)

Francesca Petrera (OGS, Trieste, Italy)

Tamara Copetti

Chiara Migliore

Melania Eva Zanchetta

Rossella Baldini

Publications

Selected papers

Baldini R, Mascaro M, Meroni G. The MID1 gene product in physiology and disease. Gene (2020), in press Apr 10;144655. PMID: 32283114 doi: 10.1016/j.gene.2020.144655

Lazzari E, El-Halawany M, De March M, Valentino F, Cantatore F, Migliore C, Onesti S and Meroni G. Analysis of the Zn-binding domains of TRIM32, the E3 ubiquitin ligase mutated in Limb Girdle Muscular Dystrophy 2H. Cells (2019) 8, 254; doi:10.3390/cells8030254. PMID: 30884854

Zanchetta ME; Napolitano LM; Maddalo D; Meroni G. The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35. Biochim Biophys Acta MCR. (2017) Jul 29;1864(10):1844-1854. doi: 10.1016/j.bbamcr.2017.07.014

Lazzari E, Meroni G. TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: From muscular dystrophy to tumours. Int J Biochem Cell Biol. 2016 Oct; 79:469-477.

Migliore C, Athanasakis E, Dahoun S, Wonkam A, Lees M, Calabrese O, Connell F, Lynch SA, Izzi C, Pompilii E, Thakur S, van Maarle M, Wilson LC, Meroni G. Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations. Eur J Med Genet. 2013 Aug;56(8):404-10.

Napolitano LM, Jaffray EG, Hay RT, Meroni G. Functional interactions between ubiquitin E2 enzymes and TRIM proteins. Biochem J. 2011 Mar 1;434(2):309-19.

Lancioni A, Pizzo M, Fontanella B, Ferrentino R, Napolitano LM, De Leonibus E, Meroni G. Lack of Mid1, the mouse ortholog of the Opitz syndrome gene, causes abnormal development of the anterior cerebellar vermis. J Neurosci. 2010 Feb 24;30(8):2880-7.

Cairo S, De Falco F, Pizzo M, Salomoni P, Pandolfi PP, Meroni G. PML interacts with Myc, and Myc target gene expression is altered in PML-null fibroblasts. Oncogene. 2005 Mar 24;24(13):2195-203.

Reymond A*, Meroni G*, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A. The tripartite motif family identifies cell compartments. EMBO J. 2001 May 1;20(9):2140-51.

Cainarca S, Messali S, Ballabio A, Meroni G. Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. Hum Mol Genet. 1999 Aug;8(8):1387-96.

Notices

PhD student position available, see the call at www.biologia.units.it/corsi/10/

Last update: 04-15-2024 - 23:30

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