Chemical modifiers tag-team to regulate essential mechanism of life
Scientists at the Gladstone Institutes have made a key observation about one of the most fundamental biological processes: gene transcription.
A gene's job is to provide a cell with the instructions to create
Chemical modifiers tag-team to regulate essential mechanism of life
Scientists at the Gladstone Institutes have made a key observation about one of the most fundamental biological processes: gene transcription.
A gene's job is to provide a cell with the instructions to create a specific protein. The first step of this process is called transcription, during which the DNA is copied into RNA. The scribe is an enzyme called RNA polymerase II, but the polymerase doesn't work alone. Several proteins interact with the polymerase's long tail to produce chemical modifications that regulate critical steps of the processing of cellular RNA.
For decades, scientists thought that one modification, phosphorylation, ran the show. Its function is so essential that it occurs during gene transcription in cells ranging from yeast to humans. In 2013, Melanie Ott, MD, Ph.D., a senior investigator at Gladstone, discovered that another modification, called acetylation, also occurs on the regulatory tail of the polymerase during gene transcription in more complex organisms like mammals. No one knew what acetylation was doing, though, until now.
"There's so much evidence that phosphorylation plays an important role in transcription in many different species," says Ott, who published a new paper on the topic in the scientific journal Molecular Cell. "We show that acetylation provides a unique avenue for higher order species to regulate thousands of genes. Before, we only knew of its existence; now, we know how it functions."
Three Waves of Modifications
Ott's team revealed that acetylation and phosphorylation tag-team to guide the RNA polymerase through the different steps of transcription.
To start transcribing a gene, the polymerase tail must be marked by phosphorylation at a specific spot. However, for the polymerase to continue and complete making the RNA copy, that mark needs to be removed. In the new paper, Ott and her colleagues show that a key role for acetylation is to recruit a family of proteins called RPRD to the polymerase, which contain an enzyme that can erase the phosphorylation.
"Our report is the first to indicate that acetylation enhances the binding of the RPRD proteins to the polymerase," says Ibraheem Ali, Ph.D., a postdoctoral fellow in Ott's lab who is first author on the new paper. "What we think happens is that the RPRD proteins bind to the acetylation mark, helping to remove the first phosphorylation so the polymerase can move on to the next phase of transcription."
The team also found that another protein is recruited to the polymerase to remove the acetylation mark. This step might be necessary to enable a second phosphorylation to occur at a different site on the polymerase tail, which is needed to jump-start the next stage of transcription.
"We imagine it happening in three waves," Ali explains. "The first wave is the first phosphorylation. The second wave is the acetylation, and the presence of the second wave forces the first wave to subside. And then, as acetylation is removed, the second phosphorylation can occur, which is the third wave. By the time all these waves have passed, you have a fully transcribed gene."
By regulating genes in this step-wise approach, cells can quickly and efficiently coordinate gene expression by creating checks at different stages. This extra level of regulation is particularly useful in cells that are frequently changing their function and responding to external stimuli, like immune cells or du