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Pseudouridine-modif...
Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome
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- Guzzi, Nicola (author)
- Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine
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- Muthukumar, Sowndarya (author)
- Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine
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- Cieśla, Maciej (author)
- Lund University
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- Todisco, Gabriele (author)
- Karolinska Institute,University of Pavia
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- Ngoc, Phuong Cao Thi (author)
- Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,RNA och stamcellsbiologi,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,RNA and Stem Cell Biology,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Madej, Magdalena (author)
- Karolinska Institutet,Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,RNA och stamcellsbiologi,Forskargrupper vid Lunds universitet,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,RNA and Stem Cell Biology,Lund University Research Groups
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- Munita, Roberto (author)
- Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,RNA och stamcellsbiologi,Forskargrupper vid Lunds universitet,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,RNA and Stem Cell Biology,Lund University Research Groups
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- Fazio, Serena (author)
- Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine
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- Ekström, Simon (author)
- Lund University,Lunds universitet,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,Masspektrometri,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,BioMS,Forskargrupper vid Lunds universitet,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Mass Spectrometry,Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups
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- Mortera-Blanco, Teresa (author)
- Karolinska Institutet,Karolinska Institute
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- Jansson, Monika (author)
- Karolinska Institute
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- Nannya, Yasuhito (author)
- Kyoto University
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- Cazzola, Mario (author)
- University of Pavia,Policlinico San Matteo Pavia Fondazione
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- Ogawa, Seishi (author)
- Karolinska Institute,Kyoto University
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- Malcovati, Luca (author)
- University of Pavia,Policlinico San Matteo Pavia Fondazione
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- Hellström-Lindberg, Eva (author)
- Karolinska Institutet,Karolinska Institute
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- Dimitriou, Marios (author)
- Karolinska Institute
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- Bellodi, Cristian (author)
- Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,RNA och stamcellsbiologi,Forskargrupper vid Lunds universitet,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,RNA and Stem Cell Biology,Lund University Research Groups
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(creator_code:org_t)
- 2022-03-15
- 2022
- English.
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In: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 24:3, s. 299-306
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Abstract
Subject headings
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- Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles in tumorigenesis1. Here we show that pseudouridylation (Ψ) of a stem cell-enriched tRF subtype2, mini tRFs containing a 5′ terminal oligoguanine (mTOG), selectively inhibits aberrant protein synthesis programmes, thereby promoting engraftment and differentiation of haematopoietic stem and progenitor cells (HSPCs) in patients with myelodysplastic syndrome (MDS). Building on evidence that mTOG-Ψ targets polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed isotope exchange proteomics to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains of PABPC1. Mechanistically, this hinders the recruitment of translational co-activator PABPC1-interacting protein 1 (PAIP1)3 and strongly represses the translation of transcripts sharing pyrimidine-enriched sequences (PES) at the 5′ untranslated region (UTR), including 5′ terminal oligopyrimidine tracts (TOP) that encode protein machinery components and are frequently altered in cancer4. Significantly, mTOG dysregulation leads to aberrantly increased translation of 5′ PES messenger RNA (mRNA) in malignant MDS-HSPCs and is clinically associated with leukaemic transformation and reduced patient survival. These findings define a critical role for tRFs and Ψ in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukaemia (AML).
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Guzzi, Nicola
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Muthukumar, Sown ...
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Cieśla, Maciej
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Todisco, Gabriel ...
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Ngoc, Phuong Cao ...
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Madej, Magdalena
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show more...
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Munita, Roberto
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Fazio, Serena
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Ekström, Simon
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Mortera-Blanco, ...
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Jansson, Monika
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Nannya, Yasuhito
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Cazzola, Mario
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Ogawa, Seishi
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Malcovati, Luca
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Hellström-Lindbe ...
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Dimitriou, Mario ...
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Bellodi, Cristia ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Nature Cell Biol ...
- By the university
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Lund University
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Karolinska Institutet