Regulating an RNA switch for cellular differentiation

11 November 2012

Scientists at NIMR have dissected a molecular mechanism used to regulate the tumor suppressor let-7 microRNA. The research is published in Nature Structural & Molecular Biology.

Let-7 microRNA acts as an on-off switch for cellular differentiation. In humans, let-7 functions as a major tumor suppressor and its concentration in the cell must be tightly regulated. The post-transcriptional regulation of Let-7 relies on proteins that bind to the terminal nucleic acid loop structure of the let-7 precursor RNA and either increase or decrease the efficiency of subsequent processing steps in let-7 biogenesis.

Scientists in the group of Andres Ramos (pictured), in collaboration with Steve Martin, in the Division of Physical Biochemistry, Geoff Kelly of the MRC Biomedical NMR Center, and colleagues at the Italian Cancer Institute in Genoa, have shown how the K-homology splicing regulatory protein (KSRP), which performs multiple roles in RNA regulation, recognizes an unusual G-rich sequence in the apical loop of the let-7 microRNA precursor. This non-canonical KH-RNA interaction increases the amount of the functional let-7 microRNA tumor suppressor in the cell and is prevented by binding of the repressor Lin28. Our results indicate that this competition is mediated by a conformational switch in the RNA loop that masks the nucleo-bases targeted by KSRP.

Let-7 directly regulates the expression of the RAS, HMGA2 and MYC oncogenes. Our work suggests that freezing the structure of the apical loop in the conformation accessible by KSRP would simultaneously block repression by Lin28 and increase activation by KSRP representing an effective way to up-regulate the cellular concentration of the tumor suppressor let-7 microRNA.

Andres Ramos

Figure 1

Figure 1

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Regulation of miRNA biogenesis by KSRP.

Figure 2

Figure 2

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Left. In KH3 recognition of the miRNA precursor the RNA G4 make Watson-Crick-like contacts with the protein backbone and side chains.
Right. Structure-driven point mutations of the protein change the domain specificity and impair its capability to up-regulate miRNA in functional assays.

Original article

Giuseppe Nicastro, María Flor García-Mayoral, David Hollingworth, Geoff Kelly, Stephen R Martin, Paola Briata, Roberto Gherzi & Andres Ramos (2012)

Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis

Nature Structural & Molecular Biology, Epub ahead of print Publisher abstract

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