Determinants of mRNA recognition and translation regulation by Lin28

Nucleic Acids Res. 2012 Apr;40(8):3574-84. doi: 10.1093/nar/gkr1279. Epub 2011 Dec 30.

Abstract

Lin28 is critical for stem cell maintenance and is also associated with advanced human malignancies. Our recent genome-wide studies mark Lin28 as a master post-transcriptional regulator of a subset of messenger RNAs important for cell growth and metabolism. However, the molecular basis underpinning the selective mRNA target regulation is unclear. Here, we provide evidence that Lin28 recognizes a unique motif in multiple target mRNAs, characterized by a small but critical 'A' bulge flanked by two G:C base pairs embedded in a complex secondary structure. This motif mediates Lin28-dependent stimulation of translation. As Lin28 is also known to inhibit the biogenesis of a cohort of miRNAs including let-7, we propose that Lin28 binding to different RNA types (precursor miRNAs versus mRNAs) may facilitate recruitment of different co-factors, leading to distinct regulatory outcomes. Our findings uncover a putative yet unexpected motif that may constitute a mechanistic base for the multitude of functions regulated by Lin28 in both stem cells and cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation*
  • Humans
  • Mice
  • Mutation
  • Nucleotide Motifs
  • Octamer Transcription Factor-3 / biosynthesis
  • Octamer Transcription Factor-3 / genetics
  • Protein Biosynthesis*
  • Protein Structure, Tertiary / genetics
  • RNA, Messenger / chemistry*
  • RNA-Binding Proteins / metabolism*

Substances

  • Lin28A protein, human
  • Octamer Transcription Factor-3
  • RNA, Messenger
  • RNA-Binding Proteins