Targeting the enzyme with a dual role in breast and brain health

Tousled-like kinases are enzymes that play a complex role in preserving genome stability within cells.

One in particular — tousled-like kinase 2 (TLK2) — has been getting a fair amount of attention over recent years.

More specifically, TLK2 contributes to the repair of DNA damage, helping to keep the cell’s nucleus stable.

This enzyme’s levels of activity have previously been linked to a series of health conditions, including both breast cancer and intellectual disability.

Researchers at the University of Copenhagen in Denmark — and some from the Barcelona Institute of Science and Technology in Spain and the Spanish National Cancer Research Center in Madrid — have recently confirmed previous findings.

The new study noted that high TLK2 activity is found in estrogen receptor-positive (ER-positive) breast cancer, which makes up most diagnosed breast cancer cases. Conversely, in intellectual disability, TLK2 activity is greatly diminished.

The researchers — led by Prof. Guillermo Montoya — decided to use special techniques that have allowed them to map TLK2’s structure in detail.

As they explain in a paper now published in the journal Nature Communications, these advances could change the way in which drugs are designed for breast cancer therapy, and even the treatment of intellectual disability or neurological disorders.

An ‘important and interesting enzyme’

Prof. Montoya and colleagues used a technique known as X-ray crystallography to describe TLK2’s structure in much greater detail than previously attempted, at molecular level.

The scientists took their cue from existing studies showing that people with an intellectual disability have a mutation of the TLK2 gene that affects the production of the enzyme.

In the recent research, the scientists confirm this association, acknowledging that certain genetic variants associated with this disability mean that TLK2 is rendered underactive.

Moreover, following studies that have shown that TLK2 is overactive in ER-positive breast cancer cells, the team decided to test the action of various small molecule drugs on this enzyme.

They tested these drugs — targeting TLK2 in human breast cancer cells — and found that it is possible to suppress its abnormal activity levels.

We are outlining the structure of this important and interesting enzyme. Once we know how it is structured, it will be much easier to develop drugs targeted at the enzyme, either inhibiting or strengthening it.”

Prof. Guillermo Montoya

“This study,” continues Prof. Montoya, “thus points directly to drug design, as it has identified some concrete mechanisms that must be taken into account.”

In the future, Prof. Montoya and team would like to go ahead and experiment with ways of targeting TLK2 in breast cancer and intellectual disability.

They hope that, eventually, they will be able to use their enhanced knowledge about this enzyme’s biomolecular structure to refine existing drugs used to treat these two conditions.

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