Molecular basis of human nuclear and mitochondrial tRNA 3' processing

Nat Struct Mol Biol. 2025 Apr;32(4):613-624. doi: 10.1038/s41594-024-01445-w. Epub 2025 Jan 2.

Abstract

Eukaryotic transfer RNA (tRNA) precursors undergo sequential processing steps to become mature tRNAs. In humans, ELAC2 carries out 3' end processing of both nucleus-encoded (nu-tRNAs) and mitochondria-encoded (mt-tRNAs) tRNAs. ELAC2 is self-sufficient for processing of nu-tRNAs but requires TRMT10C and SDR5C1 to process most mt-tRNAs. Here we show that TRMT10C and SDR5C1 specifically facilitate processing of structurally degenerate mt-tRNAs lacking the canonical elbow. Structures of ELAC2 in complex with TRMT10C, SDR5C1 and two divergent mt-tRNA substrates reveal two distinct mechanisms of pre-tRNA recognition. While canonical nu-tRNAs and mt-tRNAs are recognized by direct ELAC2-RNA interactions, processing of noncanonical mt-tRNAs depends on protein-protein interactions between ELAC2 and TRMT10C. These results provide the molecular basis for tRNA 3' processing in both the nucleus and the mitochondria and explain the organelle-specific requirement for additional factors. Moreover, they suggest that TRMT10C-SDR5C1 evolved as a mitochondrial tRNA maturation platform to compensate for the structural erosion of mt-tRNAs in bilaterian animals.

MeSH terms

  • Cell Nucleus* / metabolism
  • Humans
  • Methyltransferases / chemistry
  • Methyltransferases / metabolism
  • Mitochondria* / metabolism
  • Models, Molecular
  • Neoplasm Proteins
  • Nucleic Acid Conformation
  • RNA Processing, Post-Transcriptional*
  • RNA, Mitochondrial
  • RNA, Transfer* / chemistry
  • RNA, Transfer* / genetics
  • RNA, Transfer* / metabolism
  • tRNA Methyltransferases / chemistry
  • tRNA Methyltransferases / metabolism

Substances

  • RNA, Transfer
  • ELAC2 protein, human
  • TRMT10c protein, human
  • tRNA Methyltransferases
  • RNA, Mitochondrial
  • Methyltransferases
  • Neoplasm Proteins