PhD defence J. (Joyce) Wolf-van der Meer

Below is a brief summary of the dissertation:

The Hao-Fountain neurodevelopmental disorder is caused by mutations in the gene coding for Ubiquitin Specific Protease 7 (USP7). Symptoms in affected individuals include global developmental delay, seizures, variably impaired intellectual development with significant speech delay, eye anomalies, behavioral anomalies, including autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD) and dysmorphic features. USP7 is also involved in the regulation of tumor suppressor p53. The gene encoding p53, TP53, is mutated in more than 50% of all human cancers. However, Hao-Fountain syndrome patients do not have an elevated chance of developing cancer. 
Ubiquitin is a small protein, that can be conjugated to other proteins. This process is called ubiquitination. Ubiquitination can have different outcomes for the substrate protein. Mostly it leads to degradation of the ubiquitinated protein. But ubiquitination can also lead to a different cellular localization, affect the affinity for binding other proteins, or alter the activity of the ubiquitinated protein. 
USP7 is a deubiquitinase, which means that USP7 is capable of cleaving ubiquitin from ubiquitinated proteins. In this thesis we have determined the most probable interactors of USP7 and the consequences for these interaction partners when cells lack functional USP7 or when USP7’s activity is chemically inhibited. From the 49 most probable interactors, 39 interactors are deubiquitinated by USP7 and 26 of them are affected in their cellular protein level. Interestingly, many of the interactors have been implicated in other neurodevelopmental disorders. Presumably, the Hao-Fountain syndrome is the result of the cumulative effect of USP7 on several substrates.