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

• Published in: Nature cell biology Vol. 24; no. 3; pp. 299 - 306
• Main Authors: Guzzi, Nicola, Muthukumar, Sowndarya, Cieśla, Maciej, Todisco, Gabriele, Ngoc, Phuong Cao Thi, Madej, Magdalena, Munita, Roberto, Fazio, Serena, Ekström, Simon, Mortera-Blanco, Teresa, Jansson, Monika, Nannya, Yasuhito, Cazzola, Mario, Ogawa, Seishi, Malcovati, Luca, Hellström-Lindberg, Eva, Dimitriou, Marios, Bellodi, Cristian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2022; Nature Publishing Group
• Subjects: 101/58; 13; 13/100; 13/106; 13/109; 13/31; 14; 38; 38/5; 38/90; 5' Untranslated Regions; 631/337/384/521; 631/337/574; 631/45/500; 631/532/2118/1542; 631/67/71; 64; 64/60; 82; Acute myeloid leukemia; Basic Medicine; Biomedical and Life Sciences; Cancer Research; Cell and Molecular Biology; Cell Biology; Cell- och molekylärbiologi; Clinical Medicine; Developmental Biology; Enrichment; Fragments; Hematologi; Hematology; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Humans; Klinisk medicin; Letter; Leukemia; Leukemia, Myeloid, Acute; Life Sciences; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Pathogenesis; Peptide Initiation Factors - metabolism; Polyadenylation; Progenitor cells; Protein biosynthesis; Protein synthesis; Proteins; Proteomics; Pseudouridine; Pseudouridylation; RNA, Transfer - genetics; RNA, Transfer - metabolism; RNA-Binding Proteins - genetics; Stem Cells; Translation; tRNA
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-022-00852-9

Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles in tumorigenesis
1
. Here we show that pseudouridylation (Ψ) of a stem cell-enriched tRF subtype
2
, 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 cancer
4
. 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).
Bellodi, Dimitriou and colleagues report that pseudouridine-modified transfer-RNA fragments modulate the translation of transcripts sharing pyrimidine-enriched sequences at their 5′ untranslated regions and their dysregulation impacts myelodysplastic syndrome pathogenesis.