Abstract
Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28’s RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions.
Highlights
Lin28 is a conserved RNA-binding protein in higher eukaryotes that regulates several important cellular functions associated with development, glucose metabolism, differentiation and pluripotency
It was first described as a heterochronic gene in Caenorhabditis elegans (C. elegans), since mutations within lin-28 disturbed the developmental timing of the worm and accelerated differentiation of hypodermal seam cells and vulva stem cells [1,2]
Subsequent experiments revealed that Lin28 is expressed early in nematode embryonic and larval development, but its expression is down-regulated by lin-4 and let-7 miRNA as differentiation proceeds [2,3]
Summary
Lin (cell lineage abnormal 28) is a conserved RNA-binding protein in higher eukaryotes that regulates several important cellular functions associated with development, glucose metabolism, differentiation and pluripotency. It was first described as a heterochronic gene in Caenorhabditis elegans (C. elegans), since mutations within lin-28 disturbed the developmental timing of the worm and accelerated differentiation of hypodermal seam cells and vulva stem cells [1,2]. Lin28a/Lin28b contain two RNA-binding domains (RBDs): an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD) comprised of two retroviral type CCHC Zn knuckles (ZnK). Amino acids belonging to CSD or ZKD are shaded in blue or green, respectively
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