The genetic information on a DNA molecule is transcribed into an mRNA which later translates the information into proteins that carry out millions of cellular functions. There are sometimes when this process stutters or stalls and the respective cell have to decide whether to keep going or give up. Researchers at the Stowers Institute for Medical Research revealed that a molecule called elongin-A plays a dual in this process.
Under normal conditions, when the cells are unstressed, the molecule keeps the process of transcription moving. The genes are expressed and RNA is synthesized more quickly. When cells are stressed or the DNA is damaged, transcription runs into a glitch. Here elongin-A marks the transcription machinery to be disassembled. It acts as both a facilitator and a destroyer as well. Scientists at the Stowers Institute have now discovered how the molecule switches between these two alternate identities. The findings are reported in the Journal of Biological Chemistry.
Transcription is a stepwise process that converts the genetic information in the DNA into a working copy of RNA. Transcriptional regulation and gene expression is a very delicate balancing act for any cell. If the process stucks in between, transcription is physically blocked. This might have a devastating effect if the gene is a tumor suppressor gene or an essential survivor gene. Plus the process doesn’t start again until the stalled machinery is removed. Understanding the mechanism that how elongin-A helps to disassemble the transcription machinery gives us insight into diseases like cancer that occur due to inappropriate turning on or off of the genes.
Elongin-A plays two parts
It has been around three decades that scientists are studying the fundamental mechanisms that drive transcription. Many of their discoveries have centered on elongin A. It is a molecule that plays two parts in this process.
- It helps to elongate the strands of RNA, coming out of the transcription machinery, by speeding up the rate at which DNA is copied into RNA.
- It helps to remove stalled polymerases by bringing in molecules that tag the machinery for disposal.
In the former role, elongin A partners with its sister proteins elongin B and C. However, in the latter role, it also brings in another protein called Cul5. The research team decided to track its association with Cul5 in order to monitor its behavior in the cell.
The researchers induced DNA damage by irradiating an entire plate of cells with ultraviolet radiations. The experiment revealed that elongin A formed a complex in the irradiated cells, but not in healthy cells.
In a separate experiment, a single line of damage across the DNA was drawn using a laser. The damage was visual under the microscope. The researchers fluorescently labeled elongin-A and Cul5 and found that these proteins rapidly accumulated at regions of localized DNA damage.
Furthermore, the researchers intended to determine what kind of signals could cause elongin-A to assemble with Cul5 and form a “ubiquitin ligase” complex. For this purpose, the cells were treated with a slew of drugs that,
- Generated lesions in the DNA
- Blocked the polymerase
- Simulated nutrient starvation
All of these were found to trigger elongin-A’s shift in roles. The researchers plan to chase this avenue in future studies and continue to explore the variety of signals that shape the behavior of elongin-A in hopes of elucidating its roles in the cell.