tRNA fragments (tRFs) guide Ago to regulate gene expression post-transcriptionally in a Dicer-independent manner

• Published in: RNA (Cambridge) Vol. 24; no. 8; pp. 1093 - 1105
• Main Authors: Kuscu, Canan, Kumar, Pankaj, Kiran, Manjari, Su, Zhangli, Malik, Asrar, Dutta, Anindya
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.08.2018
• Subjects: 3' Untranslated regions; Argonaute Proteins - genetics; Autoantigens - metabolism; Cell culture; Cell Line; Complementarity; DEAD-box RNA Helicases - genetics; Eukaryotic Initiation Factors - genetics; Gene expression; Gene Expression Regulation - genetics; HEK293 Cells; Humans; Nucleotide sequence; Post-transcription; Protein Processing, Post-Translational - genetics; Ribonuclease III - genetics; RNA Interference; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; RNA, Transfer - genetics; RNA-Binding Proteins - metabolism; RNA-mediated interference; tRNA; post-transcriptional gene regulation; tRF; small noncoding RNA; tRNA fragments
• ISSN: 1355-8382; 1469-9001
• DOI: 10.1261/rna.066126.118

tRNA related RNA fragments (tRFs), also known as tRNA-derived RNAs (tdRNAs), are abundant small RNAs reported to be associated with Argonaute proteins, yet their function is unclear. We show that endogenous 18 nucleotide tRFs derived from the 3' ends of tRNAs (tRF-3) post-transcriptionally repress genes in HEK293T cells in culture. tRF-3 levels increase upon parental tRNA overexpression. This represses target genes with a sequence complementary to the tRF-3 in the 3' UTR. The tRF-3-mediated repression is Dicer-independent, Argonaute-dependent, and the targets are recognized by sequence complementarity. Furthermore, tRF-3:target mRNA pairs in the RNA induced silencing complex associate with GW182 proteins, known to repress translation and promote the degradation of target mRNAs. RNA-seq demonstrates that endogenous target genes are specifically decreased upon tRF-3 induction. Therefore, Dicer-independent tRF-3s, generated upon tRNA overexpression, repress genes post-transcriptionally through an Argonaute-GW182 containing RISC via sequence matches with target mRNAs.