DNA-protein crosslinks (DPCs) are covalent bonds formed between DNA and proteins,
creating a physical link between the two. These crosslinks can be caused by
environmental factors including radiation, chemicals, or naturally during cellular
metabolism. They are particularly harmful because they interfere with essential
biological processes such as DNA replication, transcription, and repair.
DPCs are considered a form of DNA damage, and if not properly repaired, they can
lead to mutations, genomic instability, or cell death. Cells have specific repair
mechanisms to handle DPCs, such as proteolytic pathways that degrade the protein
portion of the crosslink, allowing DNA repair enzymes to access and fix the DNA
damage.
The long-term goal of our laboratory is to understand how DPCs are recognized and
repaired.
LUBAC (Linear Ubiquitin Chain Assembly Complex) is a protein complex involved in
regulating immune responses and inflammation by catalyzing the formation of linear
ubiquitin chains on target proteins. Ubiquitination is a process where ubiquitin, a small
regulatory protein, is attached to other proteins, marking them for degradation,
signaling, or modifying their activity. Unlike other forms of ubiquitination, LUBAC
specifically adds ubiquitin in a linear manner, where ubiquitins are linked through their
amino-terminal methionine (M1 linkage), instead of the more common lysine residues.
Our goal is to determine how LUBAC exerts its inhibitory effects.
Many proteins that are essential for controlling cellular processes have proven
difficult to target with traditional small-molecule drugs. These proteins often act
through interactions with other proteins, and the surfaces involved are typically large
and flat, which makes them hard for small molecules to bind.
Our laboratory is engineering artificial proteins designed to bind these important
targets with high specificity. In collaboration with Despoina Mavridou, we are
developing methods to deliver these engineered proteins to target tissues using
attenuated bacterial strains.
Our overarching goal is to block or induce protein-protein interactions at will, allowing
us to modulate cellular physiological responses.