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These proteins are also called transcriptional activators because of their ability to induce the transcription of genes into RNA messages, which are required for cells to function properly
.
However, little was known about these proteins, and until now it was unclear how many activators might be present in human cells
The research was led by Mikko Taipale, associate professor of molecular genetics at the Donnelly Center for Cell and Biomolecular Research at the Temerty School of Medicine, in collaboration with the Lunenfeld-Tanenbaum Research Institute.
Senior Investigator Anne-Claude Gingras, Sinai Health System and University of Texas Professor of Molecular Genetics
.
The work was led by Taipale graduate student Nader Alerasool, who defended his doctoral thesis last month -- just a day after the study was published online in Molecular Cell, ahead of this week's Published in print
.
In this article, the researchers describe the first unbiased proteome-scale study that increased the number of known transcriptional activators from a handful to approximately 250
.
They also determined how these proteins combine with other cellular mechanisms to turn on genes, and how dysregulation of the proteins contributes to cancer
"This study is a classic fishing expedition, and we didn't know what we were going to find," said Taipale, Canada Research Chair in Functional Proteomics and Proteostasis
.
"Grant reviewers generally disapprove of non-hypothesis-driven research, but that's the beauty of proteomics
"We now have a better understanding of which proteins are strong activators
.
We can start to understand how they activate transcription
To find the activators, the researchers tested most of the 20,000 human proteins for their ability to activate gene expression in human cells
.
Many activators are transcription factors (TFs), which bind directly to DNA and turn on their target genes, while others are accessory proteins or cofactors that bind TFs and together activate their target genes
They also found that highly similar transcription factors can talk to different cofactors, which explains why two transcription factors with essentially the same DNA-binding specificity can trigger different gene expression programs
.
"These activators are not activators in all contexts
.
It may be because they activate gene X, but may actually inhibit gene Y.
Transcriptional activation occurs through the interaction of so-called transcriptional activation domains, which are present in transcription factors, with activators
.
Since the activation domain sequence is not conserved, it cannot be precisely determined computationally
For this reason, the team cut 75 activators into pieces and tested each piece for its ability to activate transcription
.
They identified about 40 activation domains with this method
They also used AlphaFold, a revolutionary bioinformatic tool for predicting protein structures, to find the interface between TFs and their activators
.
Although AlphaFold wasn't originally designed to predict protein-protein interactions, this unexpected function was one of Taipale's highlights
.
The software will become a standard tool for this type of research looking for functional connections between proteins, he said
.
"This was almost impossible to do computationally before," Taipale said
.
While many of the proteins identified were novel, some were previously detected in tumors where a TF and its accessory protein were permanently linked in an oncogenic fusion protein that ultimately activated the wrong gene
.
Piecing together the puzzle of how TF interacts with different activators could be an important step toward tailoring treatments
.
A challenge in therapeutic development is that transcription factors are not amenable to targeting with small-molecule drugs
.
"Transcription factors are difficult to target because they typically don't have drug pockets, but many coactivators are enzymes, which means they have pockets that can be targeted," Taipale said
.
"For example, when you have a cancer that has transcriptional pockets The fusion of factor and coactivator, you know which coactivator the transcription factor interacts with, and you can target that coactivator to stop cell proliferation
.
"
article title
Identification and functional characterization of transcriptional activators in human cells
