Communications Biology (Oct 2024)

Human DUS1L catalyzes dihydrouridine modification at tRNA positions 16/17, and DUS1L overexpression perturbs translation

  • Jin Matsuura,
  • Shinichiro Akichika,
  • Fan-Yan Wei,
  • Tsutomu Suzuki,
  • Takahiro Yamamoto,
  • Yuka Watanabe,
  • Leoš Shivaya Valášek,
  • Akitake Mukasa,
  • Kazuhito Tomizawa,
  • Takeshi Chujo

DOI
https://doi.org/10.1038/s42003-024-06942-8
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 12

Abstract

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Abstract Human cytoplasmic tRNAs contain dihydrouridine modifications at positions 16 and 17 (D16/D17). The enzyme responsible for D16/D17 formation and its cellular roles remain elusive. Here, we identify DUS1L as the human tRNA D16/D17 writer. DUS1L knockout in the glioblastoma cell lines LNZ308 and U87 causes loss of D16/D17. D formation is reconstituted in vitro using recombinant DUS1L in the presence of NADPH or NADH. DUS1L knockout/overexpression in LNZ308 cells shows that DUS1L supports cell growth. Moreover, higher DUS1L expression in glioma patients is associated with poorer prognosis. Upon vector-mediated DUS1L overexpression in LNZ308 cells, 5′ and 3′ processing of precursor tRNATyr(GUA) is inhibited, resulting in a reduced mature tRNATyr(GUA) level, reduced translation of the tyrosine codons UAC and UAU, and reduced translational readthrough of the near-cognate stop codons UAA and UAG. Moreover, DUS1L overexpression increases the amounts of several D16/D17-containing tRNAs and total cellular translation. Our study identifies a human dihydrouridine writer, providing the foundation to study its roles in health and disease.