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  • Brief Communication
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Efficiency and specificity in microRNA biogenesis

Abstract

Primary microRNA cleavage by the Drosha–Dgcr8 'Microprocessor' complex is critical for microRNA biogenesis. Yet, the Microprocessor may also cleave other nuclear RNAs in a nonspecific manner. We studied Microprocessor function using mathematical modeling and experiments in mouse and human tissues. We found that the autoregulatory feedback on Microprocessor expression is instrumental for balancing the efficiency and specificity of its activity by effectively tuning Microprocessor levels to those of its pri-miRNA substrate.

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Figure 1: The interplay between efficient miRNA processing and minimal off-target cleavage.
Figure 2: Microprocessor-dependent Dgcr8 cleavage maintains robust balance of efficiency and specificity in Microprocessor activity.

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Acknowledgements

We thank G.J. Hannon of the Cold Spring Harbor Laboratory (CSHL), F.V. Karginov (CSHL), D.R. Littman (New York University School of Medicine), R. Agami (Het Nederlands Kanker Instituut—Antoni van Leeuwenhoek) and N.V. Kim (Seoul National University) for reagents. We thank N. Shomron, D. Sprintzak, A. Horovitz, D.S. Tawfik and A. Eldar for comments on the manuscript. This work was supported by grants to E.H. from the Israel Science Foundation; the estates of F. Blau, L. Asseof, F. Sherr, C. Vener, J. Benattar, D. Francouer (Merck), Lilly Fulop, N. Baltor and M. Halphen; and the Wolfson family charitable trust. O.B. was supported by the Azrieli Foundation. E.H. is the incumbent of the Dr. Sydney Brenner Chair and the Helen and Milton A. Kimmelman Career Development Chair. N.B. is the incumbent of the Lorna Greenberg Scherzer Professorial Chair and was supported by a European Research Council Advanced Grant and a Helen and Martin Kimmel Award for Innovative Investigation. R.B. was supported by the California Institute for Regenerative Medicine (New Faculty Award RN2-00906-1) and the US National Institutes of Health (R01 NS057221).

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Contributions

Mathematical modeling was conducted by O.B. Experiments were conducted by M.M. Array data analysis and Dgcr8 reagents were provided by A.S. and E.C. The study was designed and coordinated by O.B., M.M., N.B. and E.H. The paper was written by O.B., M.M., N.B. and E.H., with input from A.S. and R.B.

Corresponding authors

Correspondence to Naama Barkai or Eran Hornstein.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 and Supplementary Table 1 (PDF 943 kb)

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Barad, O., Mann, M., Chapnik, E. et al. Efficiency and specificity in microRNA biogenesis. Nat Struct Mol Biol 19, 650–652 (2012). https://doi.org/10.1038/nsmb.2293

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