Processing of primary microRNAs by the Microprocessor complex
Abstract
Mature microRNAs (miRNAs) are generated via a two-step processing pathway to yield approximately 22-nucleotide small RNAs that regulate gene expression at the post-transcriptional level. Initial cleavage is catalysed by Drosha, a nuclease of the RNase III family, which acts on primary miRNA transcripts (pri-miRNAs) in the nucleus. Here we show that Drosha exists in a multiprotein complex, the Microprocessor, and begin the process of deconstructing that complex into its constituent components. Along with Drosha, the Microprocessor also contains Pasha (partner of Drosha), a double-stranded RNA binding protein. Suppression of Pasha expression in Drosophila cells or Caenorhabditis elegans interferes with pri-miRNA processing, leading to an accumulation of pri-miRNAs and a reduction in mature miRNAs. Finally, depletion or mutation of pash-1 in C. elegans causes de-repression of a let-7 reporter and the appearance of phenotypic defects overlapping those observed upon examination of worms with lesions in Dicer (dcr-1) or Drosha (drsh-1). Considered together, these results indicate a role for Pasha in miRNA maturation and miRNA-mediated gene regulation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the canonical pathway, pri-miRNAs are processed into pre-miRNAs by the microprocessor complex consisting of DGCR8 and Drosha.
“In this pathway, pri-miRNAs are transcribed from their genes and then processed into pre-miRNAs by the microprocessor complex, consisting of an RNA binding protein DiGeorge Syndrome Critical Region 8 (DGCR8) and a ribonuclease III enzyme, Drosha (27).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [27]
Cites
The nuclear RNase III Drosha initiates microRNA processing
Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., Rådmark, O., Kim, S., et al. (2003) · Nature · doi:10.1038/nature01957 · Cited by 5,094 · see citing works
The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans
Reinhart, B. J., Slack, F. J., Basson, M., Pasquinelli, A. E., Bettinger, J. C., Rougvie, A. E., Horvitz, H. R., & Ruvkun, G. (2000) · Nature · doi:10.1038/35002607 · Cited by 4,989 · see citing works
Role for a bidentate ribonuclease in the initiation step of RNA interference
Bernstein, E., Caudy, A. A., Hammond, S. M., & Hannon, G. J. (2001) · Nature · doi:10.1038/35053110 · Cited by 4,896 · see citing works
Self-citationExportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAsPreprint
Yi, R., Qin, Y., Macara, I. G., & Cullen, B. R. (2003) · Genes & Development · doi:10.1101/gad.1158803 · Cited by 3,020 · see citing works
The Microprocessor complex mediates the genesis of microRNAs
Gregory, R. I., Yan, K.-P., Amuthan, G., Chendrimada, T. P., Doratotaj, B., Cooch, N. S., & Shiekhattar, R. (2004) · Nature · doi:10.1038/nature03120 · Cited by 2,724 · see citing works
Nuclear Export of MicroRNA Precursors
Lund, E., Güttinger, S., Calado, Â., Dahlberg, J. E., & Kutay, U. (2003) · Science · doi:10.1126/science.1090599 · Cited by 2,705 · see citing works
MicroRNA maturation: stepwise processing and subcellular localization
Lee, Y., Jeon, K., Lee, J., Kim, S., & Kim, V. N. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf476 · Cited by 2,468 · see citing works
Asymmetry in the Assembly of the RNAi Enzyme Complex
Schwarz, D. S., Hutvágner, G., Du, T., Xu, Z., Aronin, N., & Zamore, P. D. (2003) · Cell · doi:10.1016/s0092-8674(03)00759-1 · Cited by 2,323 · see citing works
Hutvágner, G., McLachlan, J., Pasquinelli, A. E., Bálint, E., Tuschl, T., & Zamore, P. D. (2001) · Science · doi:10.1126/science.1062961 · Cited by 2,287 · see citing works
A Protein Interaction Map of Drosophila melanogaster
Giot, L., Bader, J. S., Brouwer, C., Chaudhuri, A., Kuang, B., Li, Y., Hao, Y. L., Ooi, C., Godwin, B., Vitols, E., et al. (2003) · Science · doi:10.1126/science.1090289 · Cited by 2,266 · see citing works
Role of MicroRNAs in Plant and Animal Development
Carrington, J. C., & Ambros, V. (2003) · Science · doi:10.1126/science.1085242 · Cited by 1,769 · see citing works
MicroRNA-Directed Cleavage of <i>HOXB8</i> mRNA
Yekta, S., Shih, I.-H., & Bartel, D. P. (2004) · Science · doi:10.1126/science.1097434 · Cited by 1,702 · see citing works
Grishok, A., Pasquinelli, A. E., Conte, D., Li, N., Parrish, S., Ha, I., Baillie, D. L., Fire, A., Ruvkun, G., & Mello, C. C. (2001) · Cell · doi:10.1016/s0092-8674(01)00431-7 · Cited by 1,600 · see citing works
Ketting, R. F., Fischer, S. E. J., Bernstein, E., Sijen, T., Hannon, G. J., & Plasterk, R. H. A. (2001) · Genes & Development · doi:10.1101/gad.927801 · Cited by 1,527 · see citing works
Self-citationExportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs
Bohnsack, M. T., Czaplinski, K., & Görlich, D. (2004) · RNA · doi:10.1261/rna.5167604 · Cited by 1,436 · see citing works
Cleavage of <i>Scarecrow-like</i> mRNA Targets Directed by a Class of <i>Arabidopsis</i> miRNA
Llave, C., Xie, Z., Kasschau, K. D., & Carrington, J. C. (2002) · Science · doi:10.1126/science.1076311 · Cited by 1,393 · see citing works
siRNAs can function as miRNAsPreprint
Doench, J. G., Petersen, C. P., & Sharp, P. A. (2003) · Genes & Development · doi:10.1101/gad.1064703 · Cited by 1,262 · see citing works
Single Processing Center Models for Human Dicer and Bacterial RNase III
Zhang, H., Kolb, F. A., Jaśkiewicz, Ł., Westhof, É., & Filipowicz, W. (2004) · Cell · doi:10.1016/j.cell.2004.06.017 · Cited by 1,043 · see citing works
Olsen, P. H., & Ambros, V. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9523 · Cited by 969 · see citing works
Zeng, Y., Wagner, E. J., & Cullen, B. R. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00541-5 · Cited by 833 · see citing works
R2D2, a Bridge Between the Initiation and Effector Steps of the Drosophila RNAi Pathway
Liu, Q., Rand, T., Kalidas, S., et al. (2003) · Science · doi:10.1126/science.1088710 · Cited by 705 · see citing works
Song, J., Liu, J., Tolia, N. H., et al. (2003) · Nature Structural & Molecular Biology · doi:10.1038/nsb1016 · Cited by 583 · see citing works
Tabara, H., Yigit, E., Siomi, H., & Mello, C. C. (2002) · Cell · doi:10.1016/s0092-8674(02)00793-6 · Cited by 542 · see citing works
Han, M.-H., Goud, S., Song, L., & Fedoroff, N. V. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307969100 · Cited by 522 · see citing works
Fragile X-related protein and VIG associate with the RNA interference machinery
Caudy, A. A., Myers, M., Hannon, G. J., & Hammond, S. M. (2002) · Genes & Development · doi:10.1101/gad.1025202 · Cited by 499 · see citing works
Self-citationA micrococcal nuclease homologue in RNAi effector complexes
Caudy, A. A., Ketting, R. F., Hammond, S. M., Denli, A. M., Bathoorn, A. M. P., Tops, B. B. J., Silva, J. M., Myers, M. M., Hannon, G. J., & Plasterk, R. H. A. (2003) · Nature · doi:10.1038/nature01956 · Cited by 473 · see citing works
Self-citationHuman RNase III Is a 160-kDa Protein Involved in Preribosomal RNA Processing
Wu, H., Xu, H., Miraglia, L. J., & Crooke, S. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005494200 · Cited by 200 · see citing works
Shiohama, A., Sasaki, T., Noda, S., Minoshima, S., & Shimizu, N. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00554-0 · Cited by 142 · see citing works
Redistribution of U-snRNPs during mitosis
Spector, D. L., & Smith, H. C. (1986) · Experimental Cell Research · doi:10.1016/0014-4827(86)90560-4 · Cited by 106 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Regulation of microRNA biogenesis
Ha, M., & Kim, V. N. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3838 · Cited by 5,462 · see citing works
Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation
O'Brien, J., Hayder, H., Zayed, Y., & Peng, C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00402 · Cited by 5,287 · see citing works
The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers
Sondka, Z., Bamford, S., Cole, C. G., Ward, S. A., Dunham, I., & Forbes, S. A. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0060-1 · Cited by 1,597 · see citing works
The evolution of gene regulation by transcription factors and microRNAs
Chen, K., & Rajewsky, N. (2007) · Nature Reviews Genetics · doi:10.1038/nrg1990 · Cited by 1,547 · see citing works
Most Caenorhabditis elegans microRNAs Are Individually Not Essential for Development or Viability
Miska, E. A., Alvarez-Saavedra, E., Abbott, A. L., Lau, N. C., Hellman, A. B., McGonagle, S. M., Bartel, D. P., Ambros, V. R., & Horvitz, H. R. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030215 · Cited by 484 · see citing works
“In animals, miRNAs are transcribed as long RNA precursors (pri-miRNAs), which are processed in the nucleus by the RNase III enzyme complex Drosha-Pasha/DGCR8 to form the approximately 70-base pre-miRNAs [21–25] or are derived directly from introns [26,27].”
BackgroundHigh-throughput RNAi screening in cultured cells: a user's guide
Echeverri, C. J., & Perrimon, N. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1836 · Cited by 380 · see citing works
Hippo Signaling Regulates Microprocessor and Links Cell-Density-Dependent miRNA Biogenesis to Cancer
Mori, M., Triboulet, R., Mohseni, M., Schlegelmilch, K., Shrestha, K., Camargo, F. D., & Gregory, R. I. (2014) · Cell · doi:10.1016/j.cell.2013.12.043 · Cited by 335 · see citing works
The role of microRNAs in endometriosis and associated reproductive conditions
Ohlsson Teague, E. M. C., Print, C. G., & Hull, M. L. (2010) · Human Reproduction Update · doi:10.1093/humupd/dmp034 · Cited by 309 · see citing works
Heme is involved in microRNA processing
Faller, M., Matsunaga, M., Yin, S., Loo, J. A., & Guo, F. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1182 · Cited by 295 · see citing works
DGCR8-dependent microRNA biogenesis is essential for skin development
Yi, R., Pasolli, H. A., Landthaler, M., Hafner, M., Ojo, T., Sheridan, R., Sander, C., O'Carroll, D., Stoffel, M., Tuschl, T., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810766105 · Cited by 232 · see citing works
microRNA strand selection: Unwinding the rules
Medley, J. C., Panzade, G., & Zinovyeva, A. Y. (2021) · WIREs RNA · doi:10.1002/wrna.1627 · Cited by 225 · see citing works
General Principals of miRNA Biogenesis and Regulation in the Brain
O'Carroll, D., & Schaefer, A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.87 · Cited by 205 · see citing works
MiR-137: an important player in neural development and neoplastic transformation
Mahmoudi, E., & Cairns, M. J. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.150 · Cited by 198 · see citing works
MicroRNAs in placental health and disease
Mouillet, J.-F., Ouyang, Y., Coyne, C. B., & Sadovsky, Y. (2015) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2015.05.057 · Cited by 195 · see citing works
Biogenesis and mechanisms of microRNA‐mediated gene regulation
Rani, V., & Sengar, R. S. (2022) · Biotechnology and Bioengineering · doi:10.1002/bit.28029 · Cited by 172 · see citing works
m6A RNA Methylation Controls Neural Development and Is Involved in Human Diseases
Du, K., Zhang, L., Lee, T., & Sun, T. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1138-1 · Cited by 153 · see citing works
MicroRNAs in brown and beige fat
Goody, D., & Pfeifer, A. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2018.05.003 · Cited by 54 · see citing works
MicroRNAs in Extracellular Vesicles of Alzheimer’s Disease
Li, W., & Zheng, Y. (2023) · Cells · doi:10.3390/cells12101378 · Cited by 43 · see citing works
Breast Cancer and the Other Non-Coding RNAs
Dvorská, D., Braný, D., Ňachajová, M., Halašová, E., & Danková, Z. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063280 · Cited by 38 · see citing works
Wang, Y., Tu, M.-J., & Yu, A.-M. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1423416 · Cited by 21 · see citing works
- Authors
- Denli, A. M., Tops, B. B. J., Plasterk, R. H. A., Ketting, R. F., & Hannon, G. J.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Hannon, Gregory J.
- Venue
- Nature
- Published
- 2004-11
- Volume
- 432
- Issue
- 7014
- Pages
- 231-235
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2136991248
- Cited by
- 2,784
- References
- 29
- Citations by year
- 2026: 49 · 2025: 108 · 2024: 121 · 2023: 128 · 2022: 150 · 2021: 151 · 2020: 151 · 2019: 116 · 2018: 140 · 2017: 132 · 2016: 141 · 2015: 158 · 2014: 156 · 2013: 175 · 2012: 159
- FWCI
- 32.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- microRNA biogenesis, microprocessor complex, Drosha, pashas, pri-miRNA processing, microRNA maturation, Dicer, let-7 microRNA, post-transcriptional regulation, RNA interference, Caenorhabditis elegans, Drosophila
- MeSH terms
- Animals, Cell Line, Drosophila melanogaster, Endoribonucleases, Humans, Phenotype, Protein Binding, RNA Processing, Post-Transcriptional, RNA-Binding Proteins, Caenorhabditis elegans, Protein Structure, Tertiary, Genes, Reporter, Drosophila Proteins, Caenorhabditis elegans Proteins, MicroRNAs, Ribonuclease III, Multiprotein Complexes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
