Defining the roles of the Integrator, NEXT, and nuclear exosome complexes in Drosophila oogenesis
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Abstract
Nuclear RNA homeostasis depends on the balance of transcription, RNA processing, degradation, and transport between the nucleus and cytoplasm. RNA degradation directed by the Integrator, nuclear exosome targeting (NEXT), and nuclear exosome complexes controls the accumulation of aberrant nuclear RNA. Here, we report that Drosophila oogenesis requires the Integrator, NEXT, and nuclear exosome complexes. Depletion of Integrator, NEXT, or nuclear exosome components in Drosophila female germ cells causes infertility and accumulation of 3' extended small nuclear RNAs, promoter upstream transcripts, and cryptic transcripts. Our data highlight the essential role of nuclear RNA degradation and processing in Drosophila oogenesis and provide a catalog of RNAs whose nuclear levels are regulated by these three complexes. We propose that Integrator, NEXT, and the nuclear exosome support oogenesis by ensuring that inappropriate transcription does not overwhelm the limited supply of proteins that bind, process, and traffic RNA.
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The Integrator complex plays a role in premature RNA Polymerase II transcription termination of mRNAs and in processing of other small RNAs through mechanisms that require the RNA exosome.
“The Integrator complex is known to play a role in premature RNA Polymerase II transcription termination of mRNAs in addition to processing of other small RNAs through mechanisms that require the RNA exosome85–87.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [85]
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Structural basis of Integrator-dependent RNA polymerase II termination
Fianu, I., Ochmann, M., Walshe, J. L., Dybkov, O., Cruz, J. N., Urlaub, H., & Cramer, P. (2024) · Nature · doi:10.1038/s41586-024-07269-4 · Cited by 73 · see citing works
A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome
Wu, G., Schmid, M., Rib, L., Polák, P., Meola, N., Sandelin, A., & Jensen, T. H. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.068 · Cited by 72 · see citing works
Targeted Enhancer Activation by a Subunit of the Integrator Complex
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Wu, Y., Albrecht, T. R., Baillat, D., Wagner, E. J., & Tong, L. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616605114 · Cited by 69 · see citing works
Navarro‐Costa, P., McCarthy, A., Prudêncio, P., Greer, C., Guilgur, L. G., Becker, J. D., Secombe, J., Rangan, P., & Martinho, R. G. (2016) · Nature Communications · doi:10.1038/ncomms12331 · Cited by 67 · see citing works
RBM7 subunit of the NEXT complex binds U-rich sequences and targets 3′-end extended forms of snRNAs
Hroššová, D., Šikorský, T., Potěšil, D., Bartošovič, M., Pasulka, J., Zdráhal, Z., Štefl, R., & Vaňáčová, Š. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv240 · Cited by 64 · see citing works
Structure of the catalytic core of the Integrator complex
Pfleiderer, M. M., & Galej, W. P. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.005 · Cited by 63 · see citing works
Puno, M. R., & Lima, C. D. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803530115 · Cited by 62 · see citing works
Sabath, K., Stäubli, M. L., Marti, S., Leitner, A., Moes, M., & Jonas, S. (2020) · Nature Communications · doi:10.1038/s41467-020-17232-2 · Cited by 61 · see citing works
Winczura, K., Schmid, M., Iasillo, C., Molloy, K. R., Harder, L. M., Andersen, J., LaCava, J., & Jensen, T. H. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.037 · Cited by 60 · see citing works
Order of the Proteasomal ATPases and Eukaryotic Proteasome Assembly
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Structural basis for RNA surveillance by the human nuclear exosome targeting (NEXT) complex
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Gerlach, P., Garland, W., Lingaraju, M., Salerno-Kochan, A., Bonneau, F., Basquin, J., Jensen, T. H., & Conti, E. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.04.011 · Cited by 55 · see citing works
Rapid Screening for CRISPR-Directed Editing of the Drosophila Genome Using white Coconversion
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Self-citationHuman snRNA genes use polyadenylation factors to promote efficient transcription termination
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Rennie, S., Dalby, M., Lloret-Llinares, M., Bakoulis, S., Vaagensø, C. D., Jensen, T. H., & Andersson, R. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky244 · Cited by 53 · see citing works
Structure of the RBM7–ZCCHC8 core of the NEXT complex reveals connections to splicing factors
Falk, S., Finogenova, K., Melko, M., Benda, C., Lykke‐Andersen, S., Jensen, T. H., & Conti, E. (2016) · Nature Communications · doi:10.1038/ncomms13573 · Cited by 52 · see citing works
Integrator enforces the fidelity of transcriptional termination at protein-coding genes
daSilva, L. F., Blumenthal, E., Beckedorff, F., Cingaram, P. R., Santos, H. G. D., Edupuganti, R. R., Zhang, A., Dokaneheifard, S., Aoi, Y., Yue, J., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe3393 · Cited by 52 · see citing works
Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1
Barra, J., Gaidosh, G., Blumenthal, E., Beckedorff, F., Tayari, M. M., Kirstein, N., Karakach, T. K., Jensen, T. H., Impens, F., Gevaert, K., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz9072 · Cited by 51 · see citing works
Integrator is a key component of human telomerase RNA biogenesis
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ARS2 Is a Conserved Eukaryotic Gene Essential for Early Mammalian Development
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The Sm Complex Is Required for the Processing of Non-Coding RNAs by the Exosome
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Schwämmle, V., Hagensen, C. E., Rogowska-Wrzesińska, A., & Jensen, O. N. (2020) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra119.001777 · Cited by 48 · see citing works
Chang, T. H., Mattei, E., Gainetdinov, I. V., Colpan, C., Weng, Z., & Zamore, P. D. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.038 · Cited by 47 · see citing works
Self-citationStructural basis of INTAC-regulated transcription
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p38 MAPK /MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex
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A combinatorial approach to uncover an additional Integrator subunit
Offley, S. R., Pfleiderer, M. M., Zucco, A. J., Fraudeau, A., Welsh, S. A., Rażew, M., Galej, W. P., & Gardini, A. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112244 · Cited by 35 · see citing works
BRAT1 links Integrator and defective RNA processing with neurodegeneration
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Transcription directionality is licensed by Integrator at active human promoters
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A genetic toolkit for studying transposon control in the Drosophila melanogaster ovary
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Co-transcriptional splicing efficiency is a gene-specific feature that can be regulated by TGFβ
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Integrator complex subunit 15 controls mRNA splicing and is critical for eye development
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Neuronal differentiation requires BRAT1 complex to remove REST from chromatin
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Assembly mechanism of Integrator’s RNA cleavage module
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RNA decay via the nuclear exosome is essential for Piwi-mediated transposon silencingPreprint
Yu, C., Manolova, T., Tirián, L., Handler, D., Hohmann, U., Nemčko, F., de Montserrat, J. P. I., Collet, G. G., Schnabl, J., Blake, E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.16.694471 · Cited by 2 · see citing works
EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery
Wijeratne, H. R. S., Runnebohm, A. M., Barron, M. P., Hampton, A. J., Li, R., Peck Justice, S. A., Lenceski, S. H., Rooney, J. D., Smith-Kinnaman, W. R., Chang, G. S., et al. (2026) · doi:10.64898/2026.01.26.701775 · Cited by 1 · see citing works
Ma, T., Huntington, C. C., Song, Z., Lardelli, R. M., Nostrand, E. L. V., & Lykke‐Andersen, J. (2026) · Genes & Development · doi:10.1101/gad.353690.126
Precision in RNA degradation: helicases, ribosome and RNA polymerase stalling, and RNA modifications
Whisenant, D., Soltys, J., Estrella, J. D., & Basu, U. (2026) · Trends in Cell Biology · doi:10.1016/j.tcb.2026.04.005
The RNA exosome: mechanisms of RNA surveillance, regulation, and disease
Upadhyai, P., Quadri, N., & Chandran, D. (2026) · RNA Biology · doi:10.1080/15476286.2026.2685379
Mechanisms of transcription termination across the coding and noncoding loci of the genome
Song, A., Hu, M., & Chen, F. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-026-01005-8
- Authors
- Lee, Y., Biasini, A., Tipping, C., Hong, S. H., & Zamore, P. D.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zamore, Phillip D.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2025-10
- Volume
- 44
- Issue
- 10
- Pages
- 116329
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC12697309
- OpenAlex
- W4414478552
- Cited by
- 6
- References
- 140
- Citations by year
- 2026: 5 · 2025: 1
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of General Medical Sciences (R35 GM136275)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Integrator complex, nuclear exosome, Drosophila oogenesis, female germ cells, RNA degradation, small nuclear RNA, infertility, RNA processing
- MeSH terms
- Animals, Cell Nucleus, Drosophila melanogaster, Female, Oogenesis, RNA Stability, Drosophila Proteins, Exosomes, Exosome Multienzyme Ribonuclease Complex
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