Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome.
Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome.
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DOI：
10.1038/s41556-022-00852-9
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发表时间：
2022-03
影响因子：
21.3
通讯作者：
Bellodi C
中科院分区：
文献类型：
--
作者：
Guzzi N;Muthukumar S;Cieśla M;Todisco G;Ngoc PCT;Madej M;Munita R;Fazio S;Ekström S;Mortera-Blanco T;Jansson M;Nannya Y;Cazzola M;Ogawa S;Malcovati L;Hellström-Lindberg E;Dimitriou M;Bellodi C
转移RNA衍生片段（tRFs）是新兴的小的非编码RNA，虽然通常在癌症中改变，但在肿瘤发生中的作用不明确。在此，我们发现富含干细胞的tRF亚型（含有5′末端寡鸟嘌呤（mTOG）的迷你tRF）的假尿苷化（pseudouridylation，CYP）选择性抑制异常蛋白质合成程序，从而促进骨髓增生异常综合征（MDS）患者造血干细胞和祖细胞（HSPC）的植入和分化。基于mTOG-β靶向多聚腺苷酸结合蛋白胞质1（PABPC 1）的证据，我们采用同位素交换蛋白质组学来揭示mTOG与PABPC 1的功能性RNA识别基序（RRM）结构域之间的关键相互作用。从机制上讲，这阻碍了翻译共激活因子PABPC 1相互作用蛋白1（PAIP 1）的募集，并强烈抑制了在5′非翻译区（UTR）共享嘧啶富集序列（PES）的转录本的翻译，包括编码蛋白质机械组分并在癌症中经常改变的5′末端寡嘧啶段（TOP）。值得注意的是，mTOG失调导致恶性MDS-HSPC中5′ PES信使RNA（mRNA）的翻译异常增加，并在临床上与白血病转化和患者生存期降低相关。这些发现确定了tRFs和tRF在以进展为急性髓性白血病（AML）的高风险为特征的难治MDS亚群中的关键作用。Bellodi、Dimitriou及其同事报道，假尿苷修饰的转移RNA片段调节在其5′非翻译区共享嘧啶富集序列的转录本的翻译，其失调影响骨髓增生异常综合征的发病机制。
Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles in tumorigenesis. Here we show that pseudouridylation (Ψ) of a stem cell-enriched tRF subtype, 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) 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. 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.
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