Ribosome biogenesis bottlenecks reveal vulnerabilities in cancer
However, efficient ribosome production requires tight coordination across numerous maturation steps, and it remains unclear if elevated rDNA transcription is proportionally converted into mature ribosomes, or whether imperfect coordination constrains the output yield. Here, we quantify pre-rRNA transcription (input) and compare it with newly-assembled cytoplasmic ribosomes (output), revealing that oncogene activation reduces the efficiency of ribosome production. Using a quantitative pulse-chase sequencing approach with mathematical modeling to resolve rRNA maturation kinetics, we found that oncogene activation creates late-stage processing bottlenecks, characterized by delayed precursor maturation and increased degradation. Perturbation of late-stage ribosome biogenesis factors preferentially impaired oncogene-driven cell growth, and limited tumor growth in mouse models, suggesting that these bottlenecks represent selective vulnerabilities in cancer, created by imbalanced biosynthetic flux. Together, these findings reveal that oncogene-driven ribosome production is imperfectly coordinated across maturation steps, and suggest that capacity limits in multi-step assembly pathways may be therapeutically exploitable in cancer and other diseases.
Authors
- Qiwei Yu (ORCID: https://orcid.org/0000-0003-0610-3484)
- Sofia A. Quinodoz (ORCID: https://orcid.org/0000-0003-1862-5204)
- Clifford P. Brangwynne (ORCID: https://orcid.org/0000-0002-1350-9960)
- Yibin Kang (ORCID: https://orcid.org/0000-0002-1626-6730)
- Andrej Košmrlj (ORCID: https://orcid.org/0000-0001-6137-9200)
- Troy J. Comi (ORCID: https://orcid.org/0000-0002-3215-4026)
- Jonida Trako (ORCID: https://orcid.org/0009-0004-1462-6490)
- Aya A. Abu-Alfa
- Jing Xia
- Jordy F. Botello (ORCID: https://orcid.org/0000-0002-0163-0595)
- Sabreen Alam (ORCID: https://orcid.org/0009-0007-5710-7756)
- Yong Wei
- Lifei Jiang (ORCID: https://orcid.org/0009-0007-7291-8311)
Institutions
- Rutgers, The State University of New Jersey (US)
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Princeton University (US)
- Johns Hopkins Medicine (US)
- Ludwig Cancer Research (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-21
- DOI
- https://doi.org/10.64898/2026.04.20.719509
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- Susan G. Komen for the Cure
- Breast Cancer Research Foundation
- Princeton University
- Rutgers Cancer Institute of New Jersey
- Brewster Foundation
- Ludwig Institute for Cancer Research
- Princeton Center for Complex Materials
- Materials Research Science and Engineering Center, Harvard University
- Multidisciplinary University Research Initiative
- National Cancer Institute
- Division of Materials Research
- Air Force Office of Scientific Research