生物
假尿苷
核糖核酸
聚腺苷酸
RNA结合蛋白
细胞生物学
翻译(生物学)
癌症研究
转移RNA
信使核糖核酸
分子生物学
遗传学
基因
作者
Nicola Guzzi,Sowndarya Muthukumar,Maciej Cieśla,Gabriele Todisco,Phuong Cao Thi Ngoc,Magdalena Madej,Roberto Munita,Serena De Fazio,Simon Ekström,Teresa Mortera‐Blanco,Monika Jansson,Yasuhito Nannya,Mario Cazzola,Seishi Ogawa,Luca Malcovati,Eva Hellström‐Lindberg,Marios Dimitriou,Cristian Bellodi
标识
DOI:10.1038/s41556-022-00852-9
摘要
Abstract 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).
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