New insights into a common protein could have broad biomedical applications

Reviewed by Emily Henderson, B.Sc.November 4, 2020

A new study from the University of Colorado Boulder sheds light on a protein key to controlling how cells grow, proliferate and function and have long been implicated in tumor development.

The results, published this week in the journal Genes and development, could lead not only to new therapies for difficult-to-treat cancers, but also to provide insights into new treatments for rare neurological diseases and developmental disorders, the authors say.

These findings could have broad biomedical application. ”

Dylan Taatjes, lead author, professor in the Department of Biochemistry

Scientists have known for decades that the Cyclin Dependent Kinase 7 (CDK7) protein plays an instrumental role in helping all cell types to transcribe, or decode, the genetic instructions provided by their DNA.

As Taatjes explains, each cell contains the same vast library or genome. But a kidney cell can turn to different sections of that library for instructions than, say, a skin cell or a heart cell. Like a librarian, CDK7 helps ensure that each cell accesses the right instructions at the right time, guiding which genes are turned on and off.

Although important during human development and for normal cell function, CDK7 can be exploited by cancer cells to drive uncontrolled growth. In recent years, scientists have found that the protein can fuel some cancers to proliferate out of control, including “triple negative” breast cancers, which are more aggressive and don’t respond well to common treatments.

This discovery sparked growing interest in the development of so-called “CDK7 inhibitors,” but due to a lack of understanding of what CDK7 does, early clinical trials have been disappointing.

“We wanted to find out exactly how it really works inside human cells,” Taatjes said.

To this end, the Taatjes laboratory collaborated with scientists from two pharmaceutical companies, Syros and Paraza, as well as colleagues from other CU Boulder laboratories, the University of Colorado School of Medicine and the BioFrontiers Institute.

Using sophisticated analytical techniques, basic biochemistry and next-generation genetic sequencing, the team identified, for the first time, the hundreds of specific proteins that CDK7 turns on or off, providing unprecedented insight into its role in cells.

The study also revealed that:

• CDK7 plays a multi-step role in transcription (genome decoding), shaping what is known as “transcriptional splicing,” where unnecessary parts of the transcribed genome are eliminated to leave only those needed for the cellular task within reach. out of hand. In particular, errors in splicing have been linked to a myriad of diseases, including blood cancers.
• CDK7 acts as the “master regulator” of other key enzymes, activating them to further drive transcription programs. Defects in the execution of these programs have been linked to cognitive diseases, including Alzheimer’s disease and rare developmental disorders, including head and face deformities.
• The function of CDK7 is controlled by the company it maintains. When attached to a larger 10-protein complex known as TFIIH, it is largely inactive. But when he stops by himself, his activity increases dramatically.

Phase 1 studies are currently underway to administer the latest version of CDK7 inhibitors to patients with drug-resistant breast, colorectal, lung, ovarian and pancreatic cancers.

The results of the new study suggest such drugs are promising, Taatjes said.

“In biology, it is widely recognized that cells will compensate by activating other enzymes if a specific enzyme is inhibited,” he said, explaining the mechanism behind drug resistance. “Our results suggest that CDK7 inhibitors may have distinct therapeutic benefits, as they would not only block CDK7, but would impact the function of other enzymes.”

The research could also lead to next-generation therapies, which, instead of completely silencing the protein, would target it only in its most active and liberated phase. This could lead to more selective inhibitors that would be less harmful to healthy cells, with fewer side effects.

And because of its many roles in shaping the way human cells develop and function, other applications may be possible.

“Cancer is an obvious application, but it’s by no means the only one,” Taatjes said.