2. Academic Validation
  3. Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome

Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome

  • Nat Cell Biol. 2022 Mar;24(3):299-306. doi: 10.1038/s41556-022-00852-9.
Nicola Guzzi # 1,  Sowndarya Muthukumar # 1,  Maciej Cieśla # 1,  Gabriele Todisco 2 3,  Phuong Cao Thi Ngoc 1,  Magdalena Madej 1,  Roberto Munita 1,  Serena Fazio 1,  Simon Ekström 4,  Teresa Mortera-Blanco 2,  Monika Jansson 2,  Yasuhito Nannya 5 6,  Mario Cazzola 3 7,  Seishi Ogawa 2 5 6,  Luca Malcovati 3 7,  Eva Hellström-Lindberg 2,  Marios Dimitriou 8,  Cristian Bellodi 9
Affiliations

Affiliations

  • 1 Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden.
  • 2 Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
  • 3 Department of Molecular Medicine, University of Pavia, Pavia, Italy.
  • 4 BioMS-Swedish National Infrastructure for Biological Mass Spectrometry, Lund University, Lund, Sweden.
  • 5 Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
  • 6 Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan.
  • 7 Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
  • 8 Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden. marios.dimitriou@ki.se.
  • 9 Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden. cristian.bellodi@med.lu.se.
  • # Contributed equally.
PMID: 35292784 DOI: 10.1038/s41556-022-00852-9
Abstract

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).

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