Determinants of mRNA recognition and translation regulation by Lin28.
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.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA.
Xin-Xiang
XX
Lei
Jie
J
Xu
Wei
W
Ma
Chong
C
Qiao
Martin A
MA
Newman
Scott M
SM
Hammond
Yingqun
Y
Huang
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009154:Mutation; D059372:Nucleotide Motifs; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry*; D016601:RNA-Binding Proteins / Q000378:metabolism*
C000715187:Lin28A protein, human; D050814:Octamer Transcription Factor-3; D012333:RNA, Messenger; D016601:RNA-Binding Proteins