A novel role for nucleolin in splice site selection

Kinneret Shefer, Ayub Boulos, Valer Gotea, Maram Arafat, Yair Ben Chaim, Aya Muharram, Sara Isaac, Amir Eden, Joseph Sperling, Laura Elnitski, Ruth Sperling

Research output: Contribution to journalArticlepeer-review


Latent 5ʹ splice sites, not normally used, are highly abundant in human introns, but are activated under stress and in cancer, generating thousands of nonsense mRNAs. A previously proposed mechanism to suppress latent splicing was shown to be independent of NMD, with a pivotal role for initiator-tRNA independent of protein translation. To further elucidate this mechanism, we searched for nuclear proteins directly bound to initiator-tRNA. Starting with UV-crosslinking, we identified nucleolin (NCL) interacting directly and specifically with initiator-tRNA in the nucleus, but not in the cytoplasm. Next, we show the association of ini-tRNA and NCL with pre-mRNA. We further show that recovery of suppression of latent splicing by initiator-tRNA complementation is NCL dependent. Finally, upon nucleolin knockdown we show activation of latent splicing in hundreds of coding transcripts having important cellular functions. We thus propose nucleolin, a component of the endogenous spliceosome, through its direct binding to initiator-tRNA and its effect on latent splicing, as the first protein of a nuclear quality control mechanism regulating splice site selection to protect cells from latent splicing that can generate defective mRNAs.

Original languageEnglish
Pages (from-to)333-352
Number of pages20
JournalRNA Biology
Issue number1
StatePublished - 2022

Bibliographical note

Publisher Copyright:
© This work was authored as part of the Contributor’s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.


  • 5MODIFIER LETTER PRIME splice site selection
  • RNA sequencing
  • alternative splicing
  • bioinformatics analysis
  • endogenous spliceosome
  • latent splice sites
  • latent splicing
  • mass spectrometry
  • splicing regulation
  • suppression of splicing


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