The discovery could lead to new drugs that block proteins that cause bowel cancer

Scientists have revealed the inner workings of a key protein involved in a wide range of cellular processes, which could pave the way
for better, less toxic cancer drugs.

Using Nobel Prize-winning microscopy techniques, the researchers revealed how the tankyrase protein switches itself
on and off by self-assembling into a 3D chain-like structure.
Their study, published in the journal Nature, revealed key structural insights into the elusive but important tankyrase protein, which plays a particularly important role
in helping to trigger bowel cancer.
Scientists at Cancer Research in London believe their research will open the door to a new cancer treatment that can control tankyrase more precisely than currently there are and with fewer
side effects.
This fundamental finding could have implications
for the treatment of various cancer, diabetes, inflammation, heart and neurodegenerative diseases.

Tankyrase is an important protein that supports "Wnt signaling," which is essential for the body to maintain stem cells and carry out processes such as cell division and development, but if left unchecked, it can lead to diseases
such as bowel cancer.
Tankyrase also controls other cellular functions that are critical for cancer, such as the maintenance
of telomeres at the ends of chromosomes.

Unlike the PARP1 protein, which comes from the same "PARP family," tankyrase still knows very
little about it.
While drugs that block PARP1 have entered the clinic, scientists still don't fully understand how tankyrase is initiated, how it works, and how to block it without causing unwanted side effects
.

In this study, scientists are the first to compare the
activation mechanisms of PARP1 and tankyrase.
They believe that similar to PARP1, tankyrase works by being recruited to a specific site and "self-assembling," aggregating and altering its 3D structure to activate itself and perform its functions
.

Over the past decade, scientists have developed drugs that block tankyrase in an attempt to treat bowel cancer, but because the Wnt signaling pathway is involved in a wide range of processes, these drugs cause too many side effects to make it to clinical trials
.

To truly understand how tankyrase inhibitors work and how to develop less toxic treatments, ICR scientists began using advanced cryo-electron microscopy to discover new structural information
.
This extremely powerful microscope freezes samples at -180°C, allowing the tiny details of protein shapes to be imaged
.

This approach allowed them to visualize and capture how tankyrase "self-assembles" into fibrous chain structures and why tankyrase needs fiber formation to activate itself
.

The researchers believe that "domains" — specific regions in proteins associated with different functions — that allow tankyrases to assemble and break down into different structures are exciting targets for future cancer drugs
.
They also believe that, depending on the domain to which the drug binds, not all tankyrase inhibitors affect Wnt signaling
in the same way.

The hope is that researchers will be able to design structurally different tankyrase inhibitors — safer and more effective inhibitors, which are urgently needed to treat bowel cancer and other tankyrase-related diseases
.

Professor Sebastian Guettler, leader of the study and associate director of the Division of Structural Biology at Cancer Research London, said: "Our research provides important new information about a particular protein molecule called tankyrase, which plays an important role in bowel cancer and other diseases, but which until now has not been understood by us
.
We're catching up – we have all these drugs to stop tankyrase, but we don't have enough basic knowledge to use them for treatment
.
”

"We have shown how tankyrase is initiated and can turn from a 'lazy' enzyme into an active one
.
If we can create better, less toxic drugs to control this process, we could pave the way
for effective bowel cancer treatments in the future.
" ”

Professor Kristian Helin, chief executive of Cancer Research London, said: "These fundamental findings help us understand how the extremely important tankyrase protein works
inside cells.
Almost all bowel cancers have an overactive Wnt signal, which works through tankyrase, so they may be targeted for drug treatment
.
”

"I hope that these key advances in our understanding of tankyrase will help us overcome the limitations of currently available drug candidates, hopefully bringing us closer to a new treatment
that targets bowel cancer.
" Tankyrase is also responsible for regulating a range of processes associated with a variety of diseases, not just cancer, so this research could have broad implications
.
”