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MODOMICS: a database of RNA modification pathways. 2021 update
Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland.
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2022 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, no D1, p. D231-D235Article in journal (Refereed) Published
Abstract [en]

The MODOMICS database has been, since 2006, a manually curated and centralized resource, storing and distributing comprehensive information about modified ribonucleosides. Originally, it only contained data on the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. Over the years, prompted by the accumulation of new knowledge and new types of data, it has been updated with new information and functionalities. In this new release, we have created a catalog of RNA modifications linked to human diseases, e.g., due to mutations in genes encoding modification enzymes. MODOMICS has been linked extensively to RCSB Protein Data Bank, and sequences of experimentally determined RNA structures with modified residues have been added. This expansion was accompanied by including nucleotide 5'-monophosphate residues. We redesigned the web interface and upgraded the database backend. In addition, a search engine for chemically similar modified residues has been included that can be queried by SMILES codes or by drawing chemical molecules. Finally, previously available datasets of modified residues, biosynthetic pathways, and RNA-modifying enzymes have been updated. Overall, we provide users with a new, enhanced, and restyled tool for research on RNA modification. MODOMICS is available at https://iimcb.genesilico.pl/modomics/.

Place, publisher, year, edition, pages
Oxford University Press, 2022. Vol. 50, no D1, p. D231-D235
National Category
Biochemistry and Molecular Biology Bioinformatics and Systems Biology
Identifiers
URN: urn:nbn:se:umu:diva-192884DOI: 10.1093/nar/gkab1083ISI: 000743496700028PubMedID: 34893873Scopus ID: 2-s2.0-85125009611OAI: oai:DiVA.org:umu-192884DiVA, id: diva2:1642846
Funder
EU, Horizon 2020, 956810Knut and Alice Wallenberg FoundationSwedish Cancer Society, 190337Cancerforskningsfonden i Norrland, AMP 21-1030
Note

Issue Section: Database Issue

Available from: 2022-03-08 Created: 2022-03-08 Last updated: 2024-04-08Bibliographically approved
In thesis
1. RNA-mediated gene expression regulation
Open this publication in new window or tab >>RNA-mediated gene expression regulation
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
RNA-medierad genuttrycksreglering
Abstract [en]

The regulation of gene expression is a key mechanism that underlies all biological processes, from embryonic development to the onset and progression of various diseases, including cancer. A growing body of evidence places RNA molecules at the center of critical regulatory steps in gene expression. They serve not only as intermediate molecules between DNA and proteins but also act as regulators of processes such as alternative splicing (AS) and translation, among others. This thesis focuses on the role of RNA in gene expression regulation. Specifically, it addresses how intrinsic properties of RNA, RNA chemical modifications, and RNA binding proteins (RBPs) can control gene expression regulatory processes.

The first part tackles specific aspects of AS in neurodifferentiation. Paper I shows how RBPs affect AS in mouse embryonic stem cells (ESCs). Within this work, we identified ZFP207, a known transcription factor (TF), as an RBP with a crucial role in modulating the AS of key transcripts for neurodifferentiation. Depletion of ZFP207 in mouse ESCs led to abnormal AS patterns and a differentiated cell phenotype.

The second part (Papers II-IV) focuses on the role of RNA modifications in disease. In Paper II, the publicly available literature linking deregulations of RNA modifications and their regulatory proteins with different diseases was curated. The obtained information was integrated into the 2021 update of the MODOMICS database, the most extensive RNA modifications database to date. Papers III and IV exemplify how two different RNA marks contribute to breast cancer. Paper III shows how METTL3, the enzyme responsible for N6-methyladenosine (m6A) deposition on messenger RNA (mRNA), affects tumorigenesis by modulating AS. METTL3-mediated AS regulation can be done either by depositing m6A at the intron-exon junctions of specific transcripts or on transcripts encoding for splicing and transcription factors, such as MYC. Changes in RNA modifications of ribosomal RNA (rRNA) affect stability, folding, and interactions with other molecules, leading to perturbed translation efficiency (TE). In Paper IV, we focused on the role of 2'-O-methylation, the most abundant rRNA modification, and its catalytic enzyme, fibrillarin (FBL), in triple-negative breast cancer (TNBC). We discovered that certain proto-oncogenes associated with breast cancer displayed a reduction in TE upon FBL depletion. Additionally, we identified 7 2'-O-methylation sites that might mediate TE regulation in a TNBC cellular model. Moreover, our study uncovered alterations in the ribosomal protein composition within the ribosomes of FBL-depleted cells. Our results support the pivotal role of 2'-O-methylation in controlling the translational capabilities of ribosomes in TNBC cells.

Overall, this work encompasses multiple aspects of gene expression regulation and describes how RNA modifications and RBPs modulate the fate of specific transcripts by controlling AS or translation.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 109
Series
Doctoral thesis / Umeå University, Department of Molecular Biology ; 2301
Keywords
RNA modifications, fibrillarin, 2'-O-methylation, translation, alternative splicing, METTL3, m6A, ZFP207, breast cancer, mouse ESCs
National Category
Basic Medicine
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-223013 (URN)978-91-8070-372-7 (ISBN)978-91-8070-371-0 (ISBN)
Public defence
2024-05-03, Major Groove, Department of Molecular Biology, University hospital area, building 6L, Umeå, 09:00 (English)
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Available from: 2024-04-12 Created: 2024-04-08 Last updated: 2024-04-12Bibliographically approved

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Groza, PaulaAguilo, Francesca

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