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"Which comes first: cellular dysregulation or ribosomal RNA? This classic chicken-and-egg problem has long flummoxed scientists studying diseases associated with altered levels of ribosomes ... researchers have struggled to confirm whether unusual ribosomal readings in patients with certain cancers and congenital conditions were contributing to the diseases’ progressions or were side effects from other cellular issues.
To better understand this relationship, scientists created a new gene editing technology called Targeted Activation of Protein Translation—TAPIR, for short. ... the new technology allows them to tweak the quantities of the ribosomal RNA (rRNA) that makes up the bulk of the ribosomes themselves. By adjusting how much rRNA a cell generates and then observing how that affects a given medical condition, the team could finally establish a cause-and-effect relationship between ribosomes and disease.
The researchers first put TAPIR to the test by prompting ribosome formation in mice with a rare congenital disease that impedes rRNA creation. Once the rRNA was switched back on, the mice showed some improvement in their condition. Then, they activated rRNA in a different set of mice with pancreatic cancer, a disease associated with heightened ribosomal activity; in response, the cancer hastened its already rapid expansion.
Both results point to the same conclusion: Changes in rRNA levels are causes of disease symptoms, not symptoms themselves."
"... New Perspectives for Rare Diseases and Cancer
The results could be particularly relevant for diseases in which ribosome function is disturbed. These include ribosomopathies such as Treacher-Collins syndrome, a rare congenital disease that causes facial malformations. In a mouse model, the researchers successfully managed to partially compensate for disease-related alterations by stimulating rRNA production in a targeted way.
In addition, the research team observed that similar mechanisms also play a role in pancreatic cancer. Tumor cells seem to use increased rRNA production to maintain their rapid growth. In the mouse model for pancreatic cancer, TAPIR was able to increase rRNA production and promote the growth of the cancer cells. This shows that the increased rRNA production has a causal effect in contributing to tumor growth and is not just a side effect. ..."
From the abstract:
"Ribosomal RNA (rRNA) transcription rates vary during development, and their dysregulation is linked to diseases such as cancer and ribosomopathies. Owing to their high abundance and genomic redundancy, the functional significance of rRNA-levels remains unclear.
Here, we developed TAPIR (Targeted Activation of Protein Translation), a CRISPR-based approach to elevate rRNA-levels by inducing 47S rDNA transcription. TAPIR increased nucleolar size and enhanced protein synthesis, even in rapidly proliferating cells.
In neural stem cells, elevated translation promoted self-renewal and proliferation in vitro and in vivo.
Furthermore, TAPIR enabled the modeling and partial rescue of associated disease phenotypes.
Our findings revealed that rRNA-levels directly regulate translational output and that protein synthesis capacity can act as a key determinant of mammalian stem cell behavior."
New CRISPR Method Makes It Possible to Control Protein Production in Cells (original news release) "A research team led by Prof. Stefan Stricker at Helmholtz Munich and Ludwig Maximilian University has developed TAPIR, a CRISPR-based technology that enables precise control of protein production in cells. The method provides new insights into the regulation of stem cells, cancer, and rare diseases, while opening up new opportunities for biomedical research."
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