Proteasomal degradation mechanisms of APOBEC3 deaminases

APOBEC3 proteins are hyper-mutators of genetic material -such as DNA-, which are produced in most human cells. One of the most important functions of APOBEC enzymes is to protect the host from viral infections, especially retroviruses such as HIV-1. Retroviruses are viruses that use reverse transcriptase to copy their RNA genome into DNA and integrate it into the host cells genome. APOBEC enzymes can interfere with this process by modifying building blocks in the viral DNA, resulting in mutations that can impair viral replication. This is a form of innate immunity, which is the first line of defense against pathogens. However, APOBEC enzymes are not only antiviral agents, but also potential sources of genomic instability and cancer in humans. APOBEC enzymes can also modify DNA in the human host DNA. This can introduce mutations that can alter the function or regulation of genes, leading to diseases such as cancer. APOBEC enzymes have been implicated in various types of cancers, such as breast, lung, bladder, cervical, and head and neck cancers. The mechanisms by which APOBEC enzymes are regulated in normal and cancer cells are still unclear and under investigation. Our work has shown that APOBEC3 factors are rapidly degraded once they enter the cellular compartment that houses our DNA. Based on this finding, we hypothesize that there are currently unknown guardian factors that protect our DNA by limiting the levels of APOBEC proteins close to the DNA. In this project we aim to identify by high-throughput screening methods these guardian factors that degrade one of the strongly cancer-associated APOBEC proteins. Ultimately, we will set out to unravel how APOBEC proteins are recognized in cells and targeted for degradation, and measure whether human DNA is indeed no longer protected from hypermutated if identified guardian factors are experimentally removed from cells. Results from this project are expected to increase understanding of how APOBEC mutators are kept in check in our cells, which will be crucial for developing novel strategies for prevention and treatment of viral and neoplastic diseases in the future.