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An image of proliferating cells seen under a microscope. The nucleus of the cell (shown in yellow) is the region where the RNA polymerase II enzyme resides. Although they vary in size, each cell maintains appropriate rates of transcription necessary for cellular function. Credit: Matthew Swaffer et al., 2023
Just as an expanding company adds employees, cells need to increase the production of biomolecules inside them as they grow in size to stay healthy. In the 1970s, biologists showed that this scaled-up biosynthesis relies on faster transcription, the process by which genetic blueprints in DNA are copied into RNA molecules. However, half a century later, the mechanisms behind the accelerated transcription rate remain unclear.
Now, Stanford researchers have published a new report. study was announced on cell That they solved the case. Researchers discovered that growing cells can make the RNA they need by increasing the availability of a key enzyme called RNA polymerase II (RNAPII), which increases with cell size. This enzyme binds to DNA to produce messenger RNA (mRNA). Messenger RNA (mRNA) is an important molecule that carries instructions to the cell’s protein-producing factories.
In this way, cells of different sizes can proportionally maintain a nearly constant concentration of biomolecules and continue to function efficiently as they grow. In addition to shedding new light on fundamental cell biology, this finding is important because disruption of biosynthetic scaling likely plays a major role in cell deterioration that leads to disease and aging.
“With this study, we answered a long-standing question: How does transcription increase with cell size?” said Matthew Swaffer, lead author of the study. “As cells grow and get bigger, they have to increase the synthesis of everything inside them, and we now have a better understanding of the processes and mechanisms involved.”
Swaffer conducted the research as a postdoctoral researcher in the lab of Jan Skotheim, a professor of biology in Stanford University’s School of Humanities and Sciences. Swaffer is currently group leader at the Wellcome Center for Cell Biology at the University of Edinburgh.
In the study, the Stanford University researchers also discovered an additional mechanism that kicks in when cells get too large and don’t have enough RNAPII. Somehow, the stability of the mRNA molecule increases, allowing the cell, at least temporarily, to balance its entire biology and extend its lifespan.
“In large cells, the number of RNAPII molecules increases, leading to increased transcription, so transcription is approximately proportional to cell size, but this is not sufficient for the largest cells,” said Skotheim, senior author of the study. said. “We identified a new feedback mechanism that stabilizes mRNA when its concentration begins to decline. These two mechanisms are able to work together to maintain mRNA concentration over a wide range of cell sizes. Masu.”
Tracking vital biomolecules
To arrive at these insights, Swaffer first examined a list of biomolecules known to be essential for transcription. Swaffer then devised an experiment in which yeast cells could use only half the normal amount of each of the key biomolecules in question to drive transcription. Swaffer et al. then measured the effects on transcription associated with changes in these biochemical concentrations.
Interestingly, transcription was not affected at all by the biomolecular Swaffers tested, except for RNAPII. “The big surprise in this study was that we were able to remove half of the typical amount of these transcription factors and there was essentially no change in transcription,” Professor Scotheim said. “The only thing that caused the decrease in transcription was removing half the amount of RNAPII.”
Based on this simple discovery, researchers at Stanford University built a dynamic equilibrium model of how cell size and the rate of transcription by RNAPII remain synchronized. When transcription alone is no longer able to scale adequately within the cell, additional mechanisms are turned on that increase mRNA persistence. Dr. Swaffer is currently studying the biology behind the newly discovered stability of mRNA, when transcription alone cannot properly expand within cells.
Relationship between aging and disease
Overall, this discovery provides a new window into cell growth, maturation, and eventual decline.
For more information:
Matthew P. Swaffer et al, RNA polymerase II dynamics and mRNA stability feedback scales for mRNA abundance and cell size, cell (2023). DOI: 10.1016/j.cell.2023.10.012