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Review
. 2012 Sep;22(9):474-82.
doi: 10.1016/j.tcb.2012.06.001. Epub 2012 Jul 9.

How does Lin28 let-7 control development and disease?

James E Thornton  1 , Richard I Gregory
Affiliations
Review

How does Lin28 let-7 control development and disease?

James E Thornton et al. Trends Cell Biol. 2012 Sep.

Abstract

One of the most ancient and highly conserved microRNAs (miRNAs), the let-7 family, has gained notoriety owing to its regulation of stem cell differentiation and essential role in normal development, as well as its tumor suppressor function. Mechanisms controlling let-7 expression have recently been uncovered, specifically the role of the RNA-binding protein Lin28 - a key developmental regulator - in blocking let-7 biogenesis. This review focuses on our current understanding of the Lin28-mediated control of let-7 maturation and highlights the central role of Lin28 in stem cell biology, development, control of glucose metabolism, and dysregulation in human disease. Manipulating the Lin28 pathway for the precise control of let-7 expression may provide novel therapeutic opportunities for cancer and other diseases.

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Figures

Figure 1
Figure 1. Lin28 selectively blocks let-7 biogenesis
(a) Model for Lin28-mediated control of let-7 biogenesis. (left) In the absence of Lin28 family members, let-7 miRNAs are processed through the canonical miRNA biogenesis pathway. Transcribed by RNA polymerase II, pri-let-7 is cleaved by the microprocessor complex of DGCR8 and Drosha, yielding pre-let-7, which is exported to the cytoplasm. Pre-let-7 is then cleaved by Dicer, resulting in a mature let-7 duplex, which is asymmetrically loaded into one of several Argonaute proteins within the RNA-induced Silencing Complex (RISC). RISC-mediated repression of target mRNAs can occur through translational inhibition and deadenylation, or, if the miRNA shares perfect sequence complementarity with its target, mRNA cleavage. (right) Expression of Lin28A in the cytoplasm blocks let-7 processing by Dicer through direct RNA-protein interactions with the terminal loop of pre-let-7 and recruits the terminal uridyl transferase (TUTase) Zcchc11/TUT4 to catalyze the addition of 3′ oligouridine tail, marking pre-let-7 for degradation by unknown nucleases. Lin28B is primarily expressed in the nucleolus and binds to pri-let-7, thereby blocking the activity of the microprocessor complex through an unknown TUTase-independent mechanism. (b) Domains of Lin28A and Lin28B proteins. Lin28A and Lin28B share significant protein sequence identity and are composed of several common domains including a Cold Shock Domain (CSD, blue) and CCHC zinc fingers (green). Lin28B contains both a nuclear localization signal (NLS) and a nucleolar localization signal (NoLS), explaining its nucleolar localization. (c) Molecular basis for Lin28 interaction with pre-let-7. A cartoon representation of Lin28A binding to the terminal loop of a generic pre-let-7 miRNA based on high-resolution crystal structures. The CSD (blue) is inserted into the terminal loop, while the CCHC zinc fingers (green) dimerize around a conserved sequence motif (GGAG) proximal to the Dicer cleavage site. Binding of the zinc fingers partially unwinds the RNA duplex of pre-let-7, perhaps explaining the resistance of Lin28-bound pre-let-7 to Dicer cleavage. Figure reproduced from [24].
Figure 2
Figure 2
Balancing the Lin28/let-7 axis in development and disease.
See this image and copyright information in PMC

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