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

Area of Science:

• Molecular Biology
• RNA Biology
• Cancer Research

Background:

• Transfer RNA-derived fragments (tRFs) are small noncoding RNAs with poorly defined roles in cancer.
• Pseudouridylation (Ψ) is a key RNA modification impacting RNA function.
• Myelodysplastic syndromes (MDS) are a group of cancers with high risk of transformation to acute myeloid leukaemia (AML).

Purpose of the Study:

• To investigate the role of pseudouridylated mini tRFs containing a 5' terminal oligoguanine (mTOG-Ψ) in hematopoietic stem and progenitor cells (HSPCs) in myelodysplastic syndrome (MDS).
• To elucidate the mechanism by which mTOG-Ψ regulates protein synthesis and its impact on HSPC function and disease progression.

Main Methods:

• Isotope exchange proteomics to identify protein interactions.
• Analysis of RNA-protein interactions, specifically between mTOG-Ψ and PABPC1.
• Assessment of mRNA translation regulation based on 5' untranslated region sequences.

Main Results:

• mTOG-Ψ selectively inhibits aberrant protein synthesis by targeting polyadenylate-binding protein cytoplasmic 1 (PABPC1).
• This interaction hinders PAIP1 recruitment and represses translation of pyrimidine-enriched sequence (PES) mRNAs, including 5' terminal oligopyrimidine tracts (TOP).
• Dysregulation of mTOG leads to increased translation of 5' PES mRNA in malignant MDS-HSPCs, correlating with leukaemic transformation and reduced survival.

Conclusions:

• Pseudouridylation of mTOG is crucial for regulating protein synthesis and maintaining HSPC function in MDS.
• Aberrant mTOG regulation contributes to leukaemic transformation in MDS.
• tRFs and pseudouridylation represent potential therapeutic targets in high-risk MDS subsets.