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Our team investigates the human genetic disorder, ataxia-telangiectasia (A-T). A-T is a multisystem genome instability syndrome. It involves cerebellar degeneration that leads to progressive neuromotor dysfunction, immunodeficiency, chromosomal instability, cancer predisposition, and acute sensitivity to agents that induce double-strand breaks (DSBs) in the DNA. A–T is caused by mutations in the ATM (ATM serine/threonine kinase or ataxia–telangiectasia mutated) gene, which was cloned in 1995. ATM is located on human chromosome 11 (11q22.3) and is made up of 69 exons spread across 150kb of genomic DNA. We are principally focused on the biomolecular mechanism of action of dexamethasone since several evidences demonstrated its benefit in patients with A- T, but also the overall ATM signaling and new ATM functions are studied. The team: Michele Menotta Ph.D. Associate Professor of Biochemistry link Mauro Magnani Professor Emeritus Anastasia Ricci Postdoctoral Researcher Muhammad Junaid Iqbal Ph.D. student Gianluca Morganti Ph.D. student Past collaborators: Federica Biancucci Sara Orazi Ph.D. Chiara Spapperi Fellowship

A-Team Università degli Studi di Ubino Carlo Bo

Our team investigates the human genetic disorder, ataxia-telangiectasia (A-T). A-T is a multisystem genome instability syndrome. It involves cerebellar degeneration that leads to progressive neuromotor dysfunction, immunodeficiency, chromosomal instability, cancer predisposition, and acute sensitivity to agents that induce double-strand breaks (DSBs) in the DNA. A–T is caused by mutations in the ATM (ATM serine/threonine kinase or ataxia–telangiectasia mutated) gene, which was cloned in 1995. ATM is located on human chromosome 11 (11q22.3) and is made up of 69 exons spread across 150kb of genomic DNA. We are principally focused on the biomolecular mechanism of action of dexamethasone since several evidences demonstrated its benefit in patients with A-T, but also the overall ATM signaling and new ATM functions are studied. The team: Michele Menotta Ph.D. Associate Professor of Biochemistry link Mauro Magnani Professor Emeritus Anastasia Ricci Postdoctoral Researcher Muhammad Junaid Iqbal Ph.D. student Gianluca Morganti Ph.D. student Past collaborators: Federica Biancucci Sara Orazi Ph.D. Chiara Spapperi Fellowship

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Patents: 1 . VARIANTI DELLA PROTEINA ATM PER IL TRATTAMENTO DI PATOLOGIE CAUSATE DA ALMENO UNA MUTAZIONE DEL GENE ATM 2. Method of evaluating the response of ataxia telangiectasia patients to glucocorticoids treatment. Pubblications: Ricci A, Biancucci F, Morganti G, Magnani M, Menotta M. Dexamethasone induces p21cip1/waf1 expression via FoxO3a independently of the Lamin A/C-HDAC2 interaction in Ataxia Telangiectasia FEBS Open Bio. 2023 Jun 21. doi: 10.1002/2211-5463.13663. Anastasia Ricci, Federica Biancucci, Gianluca Morganti, Mauro Magnani and Michele Menotta New human ATM variants are able to regain ATM functions in Ataxia Telangiectasia disease. Cell. Mol. Life Sci. 79, 601 (2022). https://doi.org/10.1007/s00018-022-04625-3 Ricci A, Orazi S, Biancucci F, Magnani M, Menotta M. The nucleoplasmic interactions among Lamin A/C-pRB-LAP2α-E2F1 are modulated by dexamethasone. Sci Rep. 2021 May 12;11(1):10099. doi: 10.1038/s41598-021-89608-3 Anastasia Ricci, Federica Biancucci, Mauro Magnani and Michele Menotta. Transcriptomic profile of ataxia telangiectasia cells treated for 30 days with a low dose of dexamethasone. All Life, Volume 14, 2021 - Issue 1. doi.org/10.1080/26895293.2021.1911863 Anastasia Ricci, Luca Galluzzi, Mauro Magnani and Michele Menotta DDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia The FASEB JournalEarly View First published: 08 December 2019 Menotta M, Orazi S, Gioacchini AM, Spapperi C, Ricci A, Chessa L, Magnani M. Proteomics and transcriptomics analyses of ataxia telangiectasia cells treated with Dexamethasone. PLoS One. 2018 Apr 2;13(4):e0195388. doi: 10.1371/journal.pone.0195388. eCollection 2018. PubMed PMID: 29608596; PubMed Central PMCID: PMC5880408. Leuzzi V, D'Agnano D, Menotta M, Caputi C, Chessa L, Magnani M. Ataxia-telangiectasia: A new remitting form with a peculiar transcriptome signature. Neurol Genet. 2018 Mar 27;4(2):e228. doi: 10.1212/NXG.0000000000000228. eCollection 2018 Apr. PubMed PMID: 29600275; PubMed Central PMCID: PMC5873729. Menotta M, Biagiotti S, Orazi S, Rossi L, Chessa L, Leuzzi V, D'Agnano D, Plebani A, Soresina A, Magnani M. In vivo effects of dexamethasone on blood gene expression in ataxia telangiectasia. Mol Cell Biochem. 2018 Jan;438(1-2):153-166. doi: 10.1007/s11010-017-3122-x. Epub 2017 Jul 25. PubMed PMID: 28744812. Menotta M, Biagiotti S, Spapperi C, Orazi S, Rossi L, Chessa L, Leuzzi V, D'Agnano D, Soresina A, Micheli R, Magnani M. ATM splicing variants as biomarkers for low dose dexamethasone treatment of A-T. Orphanet J Rare Dis. 2017 Jul 5;12(1):126. doi: 10.1186/s13023-017-0669-2. PubMed PMID: 28679388; PubMed Central PMCID: PMC5498894. Menotta M, Biagiotti S, Bartolini G, Marzia B, Orazi S, Germani A, Chessa L, Magnani M. Nano-Mechanical Characterization of Ataxia Telangiectasia Cells Treated with Dexamethasone. Cell Biochem Biophys. 2017 Mar;75(1):95-102. doi: 10.1007/s12013-016-0775-0. Epub 2016 Dec 8. PubMed PMID: 27933465. Biagiotti S, Menotta M, Orazi S, Spapperi C, Brundu S, Fraternale A, Bianchi M, Rossi L, Chessa L, Magnani M. Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2-mediated antioxidant response. FEBS J. 2016 Nov;283(21):3962-3978. doi: 10.1111/febs.13901. Epub 2016 Oct 12. PubMed PMID: 27636396. Biagiotti S, Menotta M, Giacomini E, Radici L, Bianchi M, Bozzao C, Chessa L, Magnani M. Forward subtractive libraries containing genes transactivated by dexamethasone in ataxia-telangiectasia lymphoblastoid cells. Mol Cell Biochem. 2014 Jul;392(1-2):13-30. doi: 10.1007/s11010-014-2013-7. Epub 2014 Mar 14. PubMed PMID: 24627244. Menotta M, Biagiotti S, Bianchi M, Chessa L, Magnani M. Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity. J Biol Chem. 2012 Nov 30;287(49):41352-63. doi: 10.1074/jbc.M112.344473. Epub 2012 Oct 10. PubMed PMID: 23055520; PubMed Central PMCID: PMC3510833.

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Patents: 1. VARIANTI DELLA PROTEINA ATM PER IL TRATTAMENTO DI PATOLOGIE CAUSATE DA ALMENO UNA MUTAZIONE DEL GENE ATM 2. Method of evaluating the response of ataxia telangiectasia patients to glucocorticoids treatment. Pubblications: Ricci A, Biancucci F, Morganti G, Magnani M, Menotta M. Dexamethasone induces p21cip1/waf1 expression via FoxO3a independently of the Lamin A/C-HDAC2 interaction in Ataxia Telangiectasia FEBS Open Bio. 2023 Jun 21. doi: 10.1002/2211-5463.13663. Anastasia Ricci, Federica Biancucci, Gianluca Morganti, Mauro Magnani and Michele Menotta. New human ATM variants are able to regain ATM functions in Ataxia Telangiectasia disease. Cell. Mol. Life Sci. 79, 601 (2022). https://doi.org/10.1007/s00018-022-04625-3 Ricci A, Orazi S, Biancucci F, Magnani M, Menotta M. The nucleoplasmic interactions among Lamin A/C-pRB-LAP2α-E2F1 are modulated by dexamethasone. Sci Rep. 2021 May 12;11(1):10099. doi: 10.1038/s41598-021-89608-3 Anastasia Ricci, Federica Biancucci, Mauro Magnani and Michele Menotta. Transcriptomic profile of ataxia telangiectasia cells treated for 30 days with a low dose of dexamethasone. All Life, Volume 14, 2021 - Issue 1. doi.org/10.1080/26895293.2021.1911863 Anastasia Ricci, Luca Galluzzi, Mauro Magnani and Michele Menotta DDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia The FASEB JournalEarly View First published: 08 December 2019 Menotta M, Orazi S, Gioacchini AM, Spapperi C, Ricci A, Chessa L, Magnani M. Proteomics and transcriptomics analyses of ataxia telangiectasia cells treated with Dexamethasone. PLoS One. 2018 Apr 2;13(4):e0195388. doi: 10.1371/journal.pone.0195388. eCollection 2018. PubMed PMID: 29608596; PubMed Central PMCID: PMC5880408. Leuzzi V, D'Agnano D, Menotta M, Caputi C, Chessa L, Magnani M. Ataxia-telangiectasia: A new remitting form with a peculiar transcriptome signature. Neurol Genet. 2018 Mar 27;4(2):e228. doi: 10.1212/NXG.0000000000000228. eCollection 2018 Apr. PubMed PMID: 29600275; PubMed Central PMCID: PMC5873729. Menotta M, Biagiotti S, Orazi S, Rossi L, Chessa L, Leuzzi V, D'Agnano D, Plebani A, Soresina A, Magnani M. In vivo effects of dexamethasone on blood gene expression in ataxia telangiectasia. Mol Cell Biochem. 2018 Jan;438(1-2):153-166. doi: 10.1007/s11010-017-3122-x. Epub 2017 Jul 25. PubMed PMID: 28744812. Menotta M, Biagiotti S, Spapperi C, Orazi S, Rossi L, Chessa L, Leuzzi V, D'Agnano D, Soresina A, Micheli R, Magnani M. ATM splicing variants as biomarkers for low dose dexamethasone treatment of A-T. Orphanet J Rare Dis. 2017 Jul 5;12(1):126. doi: 10.1186/s13023-017-0669-2. PubMed PMID: 28679388; PubMed Central PMCID: PMC5498894. Menotta M, Biagiotti S, Bartolini G, Marzia B, Orazi S, Germani A, Chessa L, Magnani M. Nano-Mechanical Characterization of Ataxia Telangiectasia Cells Treated with Dexamethasone. Cell Biochem Biophys. 2017 Mar;75(1):95-102. doi: 10.1007/s12013-016-0775-0. Epub 2016 Dec 8. PubMed PMID: 27933465. Biagiotti S, Menotta M, Orazi S, Spapperi C, Brundu S, Fraternale A, Bianchi M, Rossi L, Chessa L, Magnani M. Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2-mediated antioxidant response. FEBS J. 2016 Nov;283(21):3962-3978. doi: 10.1111/febs.13901. Epub 2016 Oct 12. PubMed PMID: 27636396. Biagiotti S, Menotta M, Giacomini E, Radici L, Bianchi M, Bozzao C, Chessa L, Magnani M. Forward subtractive libraries containing genes transactivated by dexamethasone in ataxia-telangiectasia lymphoblastoid cells. Mol Cell Biochem. 2014 Jul;392(1-2):13-30. doi: 10.1007/s11010-014-2013-7. Epub 2014 Mar 14. PubMed PMID: 24627244. Menotta M, Biagiotti S, Bianchi M, Chessa L, Magnani M. Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity. J Biol Chem. 2012 Nov 30;287(49):41352-63. doi: 10.1074/jbc.M112.344473. Epub 2012 Oct 10. PubMed PMID: 23055520; PubMed Central PMCID: PMC3510833.

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