Ubiquitination in genetic diseases (Prof. Meroni)

Research Strand:

Principal investigator (PI):

Germana Meroni

Tel: +39 040 558 8679
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

On-going Projects

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 ubiquitination machinery is still unclear. During the ubiquitination 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 ubiquitination process as it determines the fate of the modified substrate. We are interested in studying: TRIM-E2 binding specificity definition; TRIM-E2 pairs in ubiquitination; and TRIM homo- and hetero-interactions in ubiquitination.

Schematic representation of the ubiquitination process and of the structure of TRIM E3 ubiquitin ligases

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 and 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; ii) Understanding MID1/TRIM-mediated regulation of cytoskeletal dynamics through the control of several known and novel substrates.

Microtubular localisation of MID1/TRIM18

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, and 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 catalyse different ubiquitin chain modifications in relation to the nature of the substrate with particular focus on those relevant for the dystrophic phenotype. In particular, we are interested in: i) Understanding the role of TRIM32 in the differentiation of muscle cells and motor neurons; ii) Identify the substrates post-translationally modified by TRIM32 and their ubiquitination-driven fates to unravel TRIM32 role within physiological and pathological processes and, in the long-term, towards a proper design of therapeutic intervention.

Formation of C2C12-derived myotubes

People

Current Group Members

Elisa Lazzari, Post-doctoral fellow

Lu (Shaw) Xiong, Post-doctoral fellow

Luigi D’Ambrosio, PhD student

Erica Piovesan, PhD student

Elisabetta Segatel, Master student

Alessio Puntin, Master 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 (IRCCS – Burlo Garofalo, Trieste)

Rossella Baldini

Martina Mascaro (University of Udine)

Inês Fernandes Lages

Publications

Selected papers

Martina Mascaro, Luigi D’Ambrosio#, Elisa Lazzari#, Berta Almoguera, Saoud Tahsin Swafiri, Melania Eva Zanchetta* and Germana Meroni*. A unique missense mutation in the RING domain impairs MID1 E3 Ubiquitin ligase activity and localisation and is associated with uncommon Opitz Syndrome-like signs. BBA - Molecular Basis of Disease (2024), 1870(4):167126. doi:10.1016/j.bbadis.2024.167126
Chiara Migliore, Anna Vendramin, Shane McKee, Paolo Prontera, Francesca Faravelli, Rani Sachdev, Patricia Dias, Martina Mascaro, Danilo Licastro and Germana Meroni. SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome. Genes (2022), 13, 252. doi:10.3390/genes13020252
Kumarasinghe L, Xiong L, Garcia-Gimeno MA, Lazzari E, Sanz P, Meroni G. TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases. Cells (2021) Apr 6;10(4):820. doi:10.3390/cells10040820
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.
Meroni G*, Reymond A*, Alcalay M, Borsani G, Tanigami A, Tonlorenzi R, Lo Nigro C, Messali S, Zollo M, Ledbetter DH, Brent R, Ballabio A, Carrozzo R. Rox, a novel bHLHZip protein expressed in quiescent cells that heterodimerizes with Max, binds a non-canonical E box and acts as a transcriptional repressor. EMBO J. 1997 May 15;16(10):2892-906.
Franco B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, Cox L, Maroteaux P, Sheffield L, Rappold GA, Andria G, Petit C, Ballabio A. A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell. 1995 Apr 7;81(1):15-25.

Last update: 11-29-2024 - 23:30

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