Stress-induced cleavage of transfer RNAs (tRNAs) into tRNA-derived fragments (tRFs) occurs across organisms from yeast to humans; yet, its mechanistic underpinnings and pathological consequences remain poorly defined. Small RNA profiling revealed increased abundance of a cysteine tRNA fragment (5′-tRF^Cys) during breast cancer metastatic progression. 5′-tRF^Cys was required for efficient breast cancer metastatic lung colonization and cancer cell survival. We identified Nucleolin as the direct binding partner of 5′-tRF^Cys. 5′-tRF^Cys promoted the oligomerization of Nucleolin and its bound metabolic transcripts Mthfd1l and Pafah1b1 into a higher-order transcript stabilizing ribonucleoprotein complex, which protected these transcripts from exonucleolytic degradation. Consistent with this, Mthfd1l and Pafah1b1 mediated pro-metastatic and metabolic effects downstream of 5′-tRF^Cys—impacting folate, one-carbon, and phosphatidylcholine metabolism. Our findings reveal that a tRF can promote oligomerization of an RNA-binding protein into a transcript stabilizing ribonucleoprotein complex, thereby driving specific metabolic pathways underlying cancer progression.

从酵母到人类，应激诱导的转移 RNA (tRNA) 裂解为 tRNA 衍生片段 (tRF)；然而，其机制基础和病理后果仍然不明确。小 RNA 分析揭示了乳腺癌转移过程中半胱氨酸 tRNA 片段 (5'-tRF ^{Cys ) 的丰度增加。}5'-tRF ^Cys是有效的乳腺癌转移性肺定植和癌细胞存活所必需的。^{我们确定 Nucleolin 是 5'-tRF Cys}的直接结合伴侣。5'-tRF ^Cys促进 Nucleolin 及其结合的代谢转录本 Mthfd1l 和 Pafah1b1 寡聚成高阶转录本稳定核糖核蛋白复合物，从而保护这些转录本免遭核酸外切降解。^{与此一致的是，Mthfd1l 和 Pafah1b1 介导 5'-tRF Cys}下游的促转移和代谢作用，影响叶酸、一碳和磷脂酰胆碱代谢。我们的研究结果表明，tRF 可以促进 RNA 结合蛋白寡聚化成稳定转录的核糖核蛋白复合物，从而驱动癌症进展的特定代谢途径。