Differential stability of thymidylate synthase 3'-untranslated region polymorphic variants regulated by AUF1

Rudolf Pullmann, Kotb Abdelmohsen, Ashish Lal, Jennifer L Martindale, Robert D Ladner, Myriam Gorospe

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

A 6-nucleotide insertion (I)/deletion (D) polymorphism in the 3'-untranslated region of the thymidylate synthase gene was shown to influence mRNA stability, but the molecular basis of this effect has not been elucidated. Here, studies of both endogenous and ectopically expressed thymidylate synthase alleles revealed that the mRNA-binding, decay-promoting protein AUF1 has higher affinity for allele D mRNA. AUF1 overexpression preferentially suppressed D allele mRNA levels, whereas AUF1 silencing selectively elevated D allele mRNA levels. Our results illustrate the functional consequences of ribonucleoprotein associations involving a polymorphic RNA sequence and uncover a novel mechanism of action for non-coding RNA polymorphisms.

Original languageEnglish
Pages (from-to)23456-63
Number of pages8
JournalThe Journal of biological chemistry
Volume281
Issue number33
DOIs
Publication statusPublished - 18 Aug 2006

Keywords

  • 3' Untranslated Regions
  • Alleles
  • Base Sequence
  • Cell Line, Tumor
  • Enzyme Stability
  • Gene Silencing
  • Genetic Variation
  • HeLa Cells
  • Heterogeneous-Nuclear Ribonucleoprotein D
  • Humans
  • Molecular Sequence Data
  • Polymorphism, Genetic
  • RNA Stability
  • RNA, Messenger
  • Thymidylate Synthase
  • Up-Regulation
  • Comparative Study
  • Journal Article
  • Research Support, N.I.H., Intramural

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