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

Guzzi, Nicola LU ; Muthukumar, Sowndarya LU ; Cieśla, Maciej ; Todisco, Gabriele ; Ngoc, Phuong Cao Thi LU ; Madej, Magdalena LU ; Munita, Roberto LU ; Fazio, Serena LU ; Ekström, Simon LU and Mortera-Blanco, Teresa , et al. (2022) In Nature Cell Biology 24(3). p.299-306
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Cell Biology
volume
24
issue
3
pages
299 - 306
publisher
Nature Publishing Group
external identifiers
  • scopus:85126643934
  • pmid:35292784
ISSN
1465-7392
DOI
10.1038/s41556-022-00852-9
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022, The Author(s).
id
7001f0f9-937e-4ad6-991d-b99a84720703
date added to LUP
2022-06-08 12:01:04
date last changed
2024-06-14 16:31:02
@article{7001f0f9-937e-4ad6-991d-b99a84720703,
  abstract     = {{<p>Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles in tumorigenesis<sup>1</sup>. Here we show that pseudouridylation (Ψ) of a stem cell-enriched tRF subtype<sup>2</sup>, 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)<sup>3</sup> 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 cancer<sup>4</sup>. 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).</p>}},
  author       = {{Guzzi, Nicola and Muthukumar, Sowndarya and Cieśla, Maciej and Todisco, Gabriele and Ngoc, Phuong Cao Thi and Madej, Magdalena and Munita, Roberto and Fazio, Serena and Ekström, Simon and Mortera-Blanco, Teresa and Jansson, Monika and Nannya, Yasuhito and Cazzola, Mario and Ogawa, Seishi and Malcovati, Luca and Hellström-Lindberg, Eva and Dimitriou, Marios and Bellodi, Cristian}},
  issn         = {{1465-7392}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{299--306}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cell Biology}},
  title        = {{Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome}},
  url          = {{http://dx.doi.org/10.1038/s41556-022-00852-9}},
  doi          = {{10.1038/s41556-022-00852-9}},
  volume       = {{24}},
  year         = {{2022}},
}