Host tRNA-Derived RNAs Target the 3′Untranslated Region of SARS-CoV-2

Emily N. Hendrickson, Marna E Ericson, Lynne T. Bemis

Research output: Contribution to journalArticlepeer-review


The COVID-19 pandemic revealed a need for new understanding of the mechanisms regulating host–pathogen interactions during viral infection. Transfer RNA-derived RNAs (tDRs), previously called transfer RNA fragments (tRFs), have recently emerged as potential regulators of viral pathogenesis. Many predictive studies using bioinformatic approaches have been conducted providing a repertoire of potential small RNA candidates for further analyses; however, few targets have been validated to directly bind to SARS-CoV-2 sequences. In this study, we used available data sets to identify host tDR expression altered in response to SARS-CoV-2 infection. RNA-interaction-prediction tools were used to identify sequences in the SARS-CoV-2 genome where tDRs could potentially bind. We then developed luciferase assays to confirm direct regulation through a predicted region of SARS-CoV-2 by tDRs. We found that two tDRs were downregulated in both clinical and in vitro cell culture studies of SARS-CoV-2 infection. Binding sites for these two tDRs were present in the 3′ untranslated region (3′UTR) of the SARS-CoV-2 reference virus and both sites were altered in Variants of Concern (VOCs) that emerged later in the pandemic. These studies directly confirm the binding of human tDRs to a specific region of the 3′UTR of SARS-CoV-2 providing evidence for a novel mechanism for host–pathogen regulation.

Original languageEnglish (US)
Article number1479
Issue number12
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This research was funded by a partnership between the University of Minnesota Medical School and the University of Minnesota Foundation.

Publisher Copyright:
© 2022 by the authors.


  • SARS-CoV-2
  • VOCs
  • Variants of Concern
  • host-viral interactions
  • small noncoding RNA
  • tDR
  • tRF
  • tRNA fragments
  • tRNA-derived RNAs

PubMed: MeSH publication types

  • Journal Article


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