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MicroRNA regulation by RNA-binding proteins and its implications for cancer

Key Points

  • Global downregulation of microRNA (miRNA) expression is an apparent feature of many tumours. Oncogenic or tumour-suppressive functions have been assigned to numerous miRNAs.

  • Alterations in key players of miRNA biogenesis affect mature miRNA levels in a global manner, whereas RNA-binding proteins (RBPs) regulating specific miRNAs can contribute to differences in the production of specific (subsets of) miRNAs.

  • The observation that miRNA binding to target mRNAs can repress gene expression through distinct mechanisms suggests the involvement of accessory proteins, some of which are linked to cancer.

  • Interplay between miRNAs and RBPs on target 3′ untranslated regions can rapidly modulate target expression under specific conditions. Binding of RBPs near miRNA target sites can potentially regulate miRNA function either directly by affecting miRNA binding or indirectly through a switch in RNA secondary structure.

  • The activity of RBPs is temporally and spatially regulated through changes in transcription rate, post-translational modifications and subcellular localization, and is sometimes deregulated in cancer and other diseases.

  • The data discussed in this Review illustrate several examples of mechanisms for miRNA–RBP interplay that could hold true for other miRNAs and RBPs. As some of these mechanisms are linked to oncogenesis, the challenge now is to connect the mechanisms of action to disease by applying state-of-the-art genome-wide approaches.

Abstract

Non-protein-coding transcripts have been conserved throughout evolution, indicating that crucial functions exist for these RNAs. For example, microRNAs (miRNAs) have been found to modulate most cellular processes. The protein classes of RNA-binding proteins include essential regulators of miRNA biogenesis, turnover and activity. RNA–RNA and protein–RNA interactions are essential for post-transcriptional regulation in normal development and may be deregulated in disease. In reviewing emerging concepts of the interplay between miRNAs and RNA-binding proteins, we highlight the implications of these complex layers of regulation in cancer initiation and progression.

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Figure 1: Regulation of the microRNA biogenesis pathway by processing factors.
Figure 2: RISC-associated factors regulate efficient microRNA-mediated repression.
Figure 3: Mechanisms of microRNA–RNA-binding protein interplay in various cellular processes.

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Acknowledgements

We thank A. Morris for critical reading of the manuscript and the members of the R.A. group for their suggestions. This work was supported by the EURYI (European Research Young Investigator Award), ERC (European Research Council), KWF (Koningin Wilhelmina Fonds; Dutch Cancer Foundation) and Horizon-NWO (Nederlandse Organizatie voor Wetenschappelijk Onderzoek; R.A.). We apologize to colleagues whose work was not cited because of space limitations.

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Glossary

Passenger strand

The strand of the microRNA duplex that is complementary to the guide strand and is destined for degradation upon loading of the guide strand into the microRNA-induced silencing complex (miRISC).

Seed

Six to eight nucleotides at the 5′ end of the mature microRNA that are involved in the recognition of target mRNAs.

P-bodies

Cytoplasmic foci containing proteins involved in diverse post-transcriptional processes, such as mRNA degradation.

AU-rich element

(ARE). An element that is present in certain 3′ untranslated regions. It often contains a repeat of the AUUUA motif, which has a destabilizing effect on the mRNA in which it resides.

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van Kouwenhove, M., Kedde, M. & Agami, R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 11, 644–656 (2011). https://doi.org/10.1038/nrc3107

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