PXD023122-1

PXD023122 is an original dataset announced via ProteomeXchange.

Title	Pseudouridine-modified tRNA fragments repress malignant protein synthesis and predict leukemic progression in myelodysplastic syndrome
Description	Transfer RNA (tRNA)-derived fragments (tRF) are emerging small noncoding (nc) RNAs that, while commonly altered in cancer, have poorly defined roles in tumorigenesis. Here we show that pseudouridylation (Ψ) of a stem-cell-enriched tRF subtype, mTOG, selectively inhibits malignant protein synthesis programs, thereby promoting engraftment and differentiation of myelodysplastic syndrome (MDS) hematopoietic stem and progenitor cells (HSPC). Building on evidence that mTOG-Ψ target the polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed HDX-MS to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains in PABPC1. Mechanistically, this hinders the recruitment of the translational co-activator PABPC1-interacting protein 1 (PAIP1) and strongly represses translation of transcripts sharing 5’UTR pyrimidine-enriched sequences (PES), including 5’ terminal oligopyrimidine tracts (TOP) that encode protein machinery components, and are frequently altered in cancer. Significantly, mTOG dysregulation leads to aberrantly increased 5’PES mRNA translation in malignant MDS-HSPC and is clinically associated with leukemic transformation and reduced patient survival. Taken together, these results define a critical role for tRF and Ψ in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukemia.
HostingRepository	PRIDE
AnnounceDate	2021-12-20
AnnouncementXML	Submission_2021-12-20_04:22:29.102.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simon Ekström
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-14 06:44:45	ID requested
⏵ 1	2021-12-20 04:22:29	announced

Dataset with its publication pending

submitter keyword: RNA modifications

development

hematopoiesis

pseudouridine

stem cells

tRNA fragments

translation control. HDX MS

Cristian Bellodi
contact affiliation	Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden
contact email	cristian.bellodi@med.lu.se
lab head
Simon Ekström
contact affiliation	BioMS - Swedish National Infrastructure for Biological Mass Spectrometry, Lund University, BMC D1330, 221 84 Lund, Sweden
contact email	simon.ekstrom@med.lu.se
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/12/PXD023122

PRIDE project URI

• PRIDE
  1. PXD023122
     1. Label: PRIDE project
     2. Name: Pseudouridine-modified tRNA fragments repress malignant protein synthesis and predict leukemic progression in myelodysplastic syndrome