A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of bound metabolic mRNAs

SUMMARY Stress-induced cleavage of transfer RNAs (tRNAs) into tRNA-derived fragments (tRFs) occurs across organisms from yeast to human, yet its mechanistic bases and pathological consequences remain poorly defined. By performing genome-wide small RNA profiling, we detected increased abundance of a Cysteine tRNA fragment (5’-tRF Cys ) during breast cancer metastatic progression. 5’’-tRF Cys is required for efficient breast cancer metastatic lung colonization and metastatic cell survival. We identified Nucleolin as the direct binding partner of 5’-tRF Cys . 5’-tRF Cys binding enhanced the stability of Nucleolin’s associated pro-metastatic transcripts encoding metabolic enzymes Mthfd1l and Pafah1b1. 5’-tRF Cys stabilized these transcripts by promoting Nucleolin oligomerization and the assembly of Nucleolin and its bound transcripts into a higher-order ribonucleoprotein complex. Our findings reveal that a tRF can promote oligomerization of an RNA binding protein into a stabilizing ribonucleoprotein complex containing specific target transcripts, thereby driving specific metabolic pathways underlying cancer progression.