U of T scientists reveal key processes in ribosome and protein production

Researchers at the University of Toronto have shown that an enzyme called RNA polymerase (Pol) II promotes the building of ribosome building blocks, the molecular machinery that makes all the proteins in a cell based on the genetic code. I will.

This finding reveals a previously unknown function of the nucleolar enzyme, a site of ribosome production in human cells, where no enzyme was previously found. Pol II is one of three RNA polymerases that together allow cells to transfer genetic information from DNA to RNA and then to proteins.

“Our work redefined the division of labor between the three major RNA polymerases by identifying Pol II as the key element in the regulation of nucleolar tissue underlying protein synthesis.” Karim Mehail,Professor Laboratory medicine and pathology Mr. T of U. “It also provides tools that allow other researchers to more accurately study the function of a particular nucleic acid structure throughout the genome.”

journal Nature Announced the results today.

Mehail and his colleagues discovered that inside the nucleolus, Pol II enables expression of ribosomal RNA genes. The Pol II they showed produces an R loop (hybrid DNA-RNA structure). It directly protects ribosomal RNA genes from molecular disruptors called sense intergenic noncoding RNA (or sinc RNA).

These disruptors are produced by Pol I in intergenic, nonprotein coding sequences of intergenic DNA and become more active in a variety of conditions: under environmental stress, and Pol II disruption in Ewing sarcoma.

“Pol II brakes Pol I and prevents sinc RNA from “submerging” the nucleolus. “Thus, in the discussion of this work, we integrated the names and actions of the disturbers.”

Mehail and his team have developed a new technique to test the function of the R loop at specific locations on the chromosome. They termed the “red laser” system.

“While existing tools in the field wipe out R loops throughout the genome, we wanted to test the function of R loops associated with specific loci,” Mekhail said. “We were able to turn the old technology into a modern laser guided missile, but it is still working to improve it.”

Two students at U in T were co-authors of this study – Karan (Josh) Abraham And Negin Coslaviani – And Mehail said they made an exceptional and complementary contribution to the study.

Abraham, MD/PhD students, I started working on the project in 2014.

“I pursued this task by observing Pol II enrichment in the nucleolar ribosomal DNA gene.” If evidence supports alternative models, it is the obligation of all scientists to challenge existing models. is.”

Khosraviani, a PhD student who joined the lab in 2018, said teamwork and time management are important.

“Without lab-wide support and dedication, this study could not be completed. Coordination with local and international collaborators was also essential.”

The team at Mehail collaborated with colleagues across the U of T and collaborating hospitals and collaborated with international collaborators at the University of Texas San Antonio and the University of Miami.

The next step based on this study will be investigating the dissociation of sinc RNA and nucleoli as biomarkers for various cancers, and tumors with these functions will respond to drugs that target intergenic Pol I or II. It includes whether to do.

“COVID-19 did a devastating blow, but other illnesses didn’t stop,” he temporarily closed his physical lab during the pandemic, analyzing the results. Mehail, who continued to work with his team to make it public, said. “For example, cancer is still widespread and is affecting people’s lives. We have to do everything we can and look forward to building on the progress we have made as quickly as possible. I am.”

This work was supported by the Canadian Institute of Health, Canadian Research Chair, National Institutes of Health, Ontario Department of Research and Innovation, Ontario Graduate Scholarship Program, and the Canadian Council for Natural Sciences and Engineering Studies.