Modelling of SHMT1 riboregulation predicts dynamic changes of serine and glycine levels across cellular compartments

Monti, Michele; Guiducci, Giulia; Paone, Alessio; Rinaldo, Serena; Giardina, Giorgio; Liberati, Francesca Romana; Cutruzzolà, Francesca; Tartaglia, Gian Gaetano

Modelling of SHMT1 riboregulation predicts dynamic changes of serine and glycine levels across cellular compartments

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dc.contributor.author Monti, Michele
dc.contributor.author Guiducci, Giulia
dc.contributor.author Paone, Alessio
dc.contributor.author Rinaldo, Serena
dc.contributor.author Giardina, Giorgio
dc.contributor.author Liberati, Francesca Romana
dc.contributor.author Cutruzzolà, Francesca
dc.contributor.author Tartaglia, Gian Gaetano
dc.date.accessioned 2021-11-18T06:41:20Z
dc.date.available 2021-11-18T06:41:20Z
dc.date.issued 2021
dc.description.abstract Human serine hydroxymethyltransferase (SHMT) regulates the serine-glycine one carbon metabolism and plays a role in cancer metabolic reprogramming. Two SHMT isozymes are acting in the cell: SHMT1 encoding the cytoplasmic isozyme, and SHMT2 encoding the mitochondrial one. Here we present a molecular model built on experimental data reporting the interaction between SHMT1 protein and SHMT2 mRNA, recently discovered in lung cancer cells. Using a stochastic dynamic model, we show that RNA moieties dynamically regulate serine and glycine concentration, shaping the system behaviour. For the first time we observe an active functional role of the RNA in the regulation of the serine-glycine metabolism and availability, which unravels a complex layer of regulation that cancer cells exploit to fine tune amino acids availability according to their metabolic needs. The quantitative model, complemented by an experimental validation in the lung adenocarcinoma cell line H1299, exploits RNA molecules as metabolic switches of the SHMT1 activity. Our results pave the way for the development of RNA-based molecules able to unbalance serine metabolism in cancer cells.
dc.description.sponsorship The research leading to these results has been supported by European Research Council (RIBOMYLOME 309545 to GGT and ASTRA 855923 to GGT), the H2020 projects IASIS 727658 and INFORE 25080, the Spanish Ministry of Economy and Competitiveness BFU2017-86970-P as well as the collaboration with Peter St. George-Hyslop financed by the Wellcome Trust. GGu is supported by the Barts Charity Grant. Funding from AIRC under IG2019-ID23125 project- PI FC and from Sapienza University of Rome (Grants n. RG11816430AF48E1, RM11916B46D48441, RP11715C644A5CCE, GA116154C8A94E3D to FC and RM120172A7AD98EB, RM11715C646D693E to SR) are gratefully acknowledged.
dc.format.mimetype application/pdf
dc.identifier.citation Monti M, Guiducci G, Paone A, Rinaldo S, Giardina G, Liberati FR, Cutruzzolá F, Tartaglia GG. Modelling of SHMT1 riboregulation predicts dynamic changes of serine and glycine levels across cellular compartments. Comput Struct Biotechnol J. 2021;19:3034-41. DOI: 10.1016/j.csbj.2021.05.019
dc.identifier.doi http://dx.doi.org/10.1016/j.csbj.2021.05.019
dc.identifier.issn 2001-0370
dc.identifier.uri http://hdl.handle.net/10230/49008
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Comput Struct Biotechnol J. 2021;19:3034-41
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/855923
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/727658
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86970-P
dc.rights © 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword Metabolic networks
dc.subject.keyword RNA-binding protein
dc.subject.keyword RNA-protein interactions
dc.subject.keyword Serine/Glycine metabolism
dc.title Modelling of SHMT1 riboregulation predicts dynamic changes of serine and glycine levels across cellular compartments
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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