Molecular mechanisms of tankyrase function and inhibition

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Faculty of Biochemistry and Molecular Medicine, Auditorium F101 (Aapistie 7)

Topic of the dissertation

Molecular mechanisms of tankyrase function and inhibition

Doctoral candidate

Master of Science Sven Sowa

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, Protein and Structural Biology

Subject of study

Biochemistry

Opponent

Professor Mikko Metsä-Ketelä, University of Turku

Custos

Professor Lari Lehtiö, University of Oulu

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Molecular mechanisms of tankyrase function and inhibition

Tankyrases are proteins that are present in the cells of humans and other animals, where they perform important tasks by regulating many physiological processes. They do so by chemically attaching ADP-ribose groups to other proteins, and these groups serve as signals for the cells to degrade the affected proteins. This enzymatic process is also known as “ADP-ribosylation”. While the function of tankyrases is important in healthy cells and during the development of the body, it can negatively contribute to the growth of diseased cells in conditions such as cancer and fibrosis. Previous studies have shown that molecules which prevent the ADP-ribosylation by tankyrases can help to strongly reduce the growth of cancer cells.

To better understand how tankyrases function, a unique zinc-binding motif in tankyrases was examined with the help of biophysical methods in this work. The results showed that this motif is important for the structural stability of the protein. Furthermore, an evolutionary analysis contributed to the idea that tankyrases likely play an important role for the multicellular development in animals. As part of the thesis, new molecules were developed that can effectively prevent the ADP-ribosylation function of tankyrases. These inhibitors may act as therapeutic drugs in the future and they have already seen success in the treatment of early colorectal cancer models. A method was also developed that helps to identify molecules which can prevent other proteins from interacting with tankyrases, and these may also have the potential for therapeutic applications. Such molecules may also help to better understand the interaction of tankyrases with other proteins.

In conclusion, the function and structure of tankyrases were investigated in the frame of the thesis and important insights were gained about how to target tankyrases with inhibitors. These findings have implications for the development of drugs that may be able to treat serious conditions such as cancer.
Last updated: 5.10.2022