A bipartite U1 site represses U1A expression by synergizing with PIE to inhibit nuclear polyadenylation

Fei Guan, Rose M. Caratozzolo, Rafal Goraczniak, Eric S. Ho, Samuel I. Gunderson

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

U1A protein negatively autoregulates itself by polyadenylation inhibition of its own pre-mRNA by binding as two molecules to a 3′UTR-located Polyadenylation Inhibitory Element (PIE). The (U1A)2-PIE complex specifically blocks U1A mRNA biosynthesis by inhibiting polyA tail addition, leading to lower mRNA levels. U1 snRNP bound to a 5′ss-like sequence, which we call a U1 site, in the 3′UTRs of certain papillomaviruses leads to inhibition of viral late gene expression via a similar mechanism. Although such U1 sites can also be artificially used to potently silence reporter and endogenous genes, no naturally occurring U1 sites have been found in eukaryotic genes. Here we identify a conserved U1 site in the human U1A gene that is, unexpectedly, within a bipartite element where the other part represses the U1 site via a base-pairing mechanism. The bipartite element inhibits U1A expression via a synergistic action with the nearby PIE. Unexpectedly, synergy is not based on stabilizing binding of the inhibitory factors to the 3′UTR, but rather is a property of the larger ternary complex. Inhibition targets the biosynthetic step of polyA tail addition rather than altering mRNA stability. This is the first example of a functional U1 site in a cellular gene and of a single gene containing two dissimilar elements that inhibit nuclear polyadenylation. Parallels with other examples where U1 snRNP inhibits expression are discussed. We expect that other cellular genes will harbor functional U1 sites. Published by Cold Spring Harbor Laboratory Press.

Original languageEnglish (US)
Pages (from-to)2129-2140
Number of pages12
JournalRNA
Volume13
Issue number12
DOIs
StatePublished - Dec 2007

All Science Journal Classification (ASJC) codes

  • Molecular Biology

Keywords

  • Nuclear polyadenylation
  • Pre-mRNA processing
  • U1 snRNP
  • U1A

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