The transcription of messenger RNA from DNA is at the heart of molecular biology - the first step by which heritable genetic material controls cell function. RNA polymerase II is an essential piece of cellular machinery for this process, reading DNA into mRNA molecules, which then produce specific proteins.
Most research into genetics focuses on where and when particular genes become expressed. This project addresses basic questions regarding the Pol II enyzme itself - do controls exist on the entire system? Is the cellular abundance of Pol II directly adjusted?
Is the activity of Pol II globally regulated?
All cells must be able to continuously transcribe essential, ‘house keeping’ genes, as well as those which are context- or cell-specific at any one time. At the same time, the concentration of total (m)RNA in the cell is a key homeostatic parameter, which is controlled and stable as cells grow, sometimes referred to as mRNA concentration buffering.
Some evidence points control of mRNA concentration via control of transcription - that is the amount of mRNA produced by Pol II responds to the needs of the cell.
What is not clear is if Pol II itself is regulated on a global (rather than gene-specific) level for this to occur. Does the total abundance of Pol II directly determine how much mRNA is produced? Or, conversely, do additional activators and handbrakes adjust the amount of active Pol II to meet the needs of the cell?
Check out our review and recent pre-print.
How is the ‘right amount’ of Pol II maintained?
RNA polymerase II is a complex, multi-subunit enzyme, which is assembled in the cytoplasm before being imported to the nucleus where it can carry out its function. For a single Pol II molecule to successfully produce an mRNA transcript, 12 subunits must first be individually translated, carefully put together, and shepherded to the correct genomic location.
Years of work in the field have demonstrated how this process of Pol II biogenesis occurs in the cytoplasm, and identified many of the factors necessary for both Pol II production, and turnover in some circumstances. Key open questions remain, particularly in terms of the responsiveness of this system to cellular need. Can more Pol II be produced on demand, or what limits the amount which is produced? How is the steady stoichiometry of subunits maintained?
Recently, we in parallel with other groups characterised a newly uncovered pathway for Pol II degradation in the nucleus, which forms part of the basal turnover of this enzyme as well as responding to stimuli.