Degradation mechanisms of antiviral APOBEC proteins
Gus Versteeg started his independent research group at the Max Perutz Labs Vienna in 2013. His previous work explored how ubiquitination mediates immune system activation. His group currently investigates how the abundance of immune- and cancer-related proteins is controlled by proteasomal degradation.
- Institute Max Perutz Labs, University of Vienna
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Projects within consortium
APOBEC proteins are essential host-defense factors that act by hyper-mutating viral genetic material. However, some APOBEC proteins have been shown to aberrantly target host cell DNA, contributing to hyper-mutation signatures in certain cancers. The aim of this project is to identify new cellular factors ensuring that these factors do not mutate their own DNA, and unravel how they do so at a mechanistic molecular level.
Members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of cytosine deaminases are important viral restriction factors, preventing HIV species barrier crossing. In contrast to these host-beneficial properties, recent analyses indicate that some of the different APOBEC3 family member can have detrimental effects in humans by driving cellular hyper-mutation in breast and lung cancers, thereby contributing to a broader, disadvantageous mutational landscape within these tumors.
Current data indicate that there is a yet unidentified nuclear degradation pathway limiting APOBEC accumulation in the nucleus, thereby limiting exposure of the DNA to the mutagenic action of the APOBEC3 protein. We hypothesize that efficient degradation of nuclear APOBEC3 proteins is important to prevent genotoxicity, and hence genome integrity.
This project aims to identify the key players in nuclear APOBEC3 degradation, and understand key mechanistic steps of APOBEC3 ubiquitination and proteasomal degradation using genetic screening platforms, as well as cellular and biochemical assays.
Taken together, results from this project will provide insight into nuclear control mechanisms ensuring genome stability, and how deregulation of this pathway may contribute to cancer progression.
Targeted Protein Degradation related publications by Group Versteeg