Research gives insights into rare bone disorder

Cherubism is characterized by abnormal bone tissue in the lower part of the face. University Professor Tony Pawson, Professor Frank Sicheri and post-doctoral fellow Sebastian Guettler of molecular genetics and Mount Sinai’s Samuel Lunenfeld Research Institute worked with Robert Rottapel of OCI to uncover the detailed architecture of an enzyme that forms a key component of Tankyrase, a protein linked to the disorder.

“Until now, we did not understand, from a structural perspective, how Tankyrase identifies its substrates [targets],” Sicheri, a Lunenfeld senior investigator and one of the lead authors of the study. “At atomic resolution [the molecular level], we now have a clearer picture of what these substrates may be, and have new insight into possible novel functions of Tankyrase.”

The findings are published in the Dec. 9 issue of the leading biomedical journal Cell.

Tankyrase is one protein of a family of enzymes that modify other proteins; these enzymes affect many cellular processes. The modification reactions carried out by Tankyrase can directly alter some proteins’ functions, bring proteins together in protein complexes or can mark others for removal.

Initially intrigued by Tankyrase because of its involvement in cherubism, the U of’T researchers built upon the findings of Rottapel’s laboratory.

“Our work provides answers to two big questions. Firstly, we obtained a visual snapshot of how Tankyrase recognizes its substrates and how mutations characteristic of cherubism lead to illness,” said Guettler, the first author of the study. “Secondly, we learned more about the possible cellular tasks performed by Tankyrase. The apparent abundance of potential Tankyrase targets and the variety of cellular functions they perform suggests that the complexity of Tankyrase’s biological functions has been underappreciated to date.”

Inhibiting Tankyrase function may hold promise for treating certain breast cancers as well as other cancers, and therefore the present study may help refine treatment strategies for blocking Tankyrase.