Investigating the cellular role of a novel deubiquitylating enzyme in the DNA damage response

Ubiquitin is a 76-amino-acid polypeptide that can be appended to target proteins post-translationally to modify their function and turnover in cells. As the name suggests, it is involved in a wide array of cellular functions, ranging from protein degradation to inflammatory signaling and the cell's response to DNA damage. Cells can append a single ubiquitin molecule to a target, as well as synthesize longer chains of ubiquitin linked either via internal lysine residues or to the N-terminal primary amine. This creates a vast array of different signals that are read by distinct effector proteins driving different functional outcomes within a cell. A critical aspect of ubiquitin conjugation and signaling is that it is a reversible and highly dynamic process. As with many cellular processes it is the balance between presence and absence of a signal that is important. The enzyme class that maintains this delicate equilibrium are deubiquitylating enzymes (DUBs), which act to cleave or edit the ubiquitin signal from protein substrates. Excitingly, the research community has recently reported the discovery of a novel DUB named ZUP1. This protein does not share significant homology with existing DUBs and constitutes a new class of enzymes. Interestingly, ZUP1 has been shown to localize to sites of DNA damage and promote genome stability and cell viability in response to genotoxic stress. However, ZUP1's function within cells remains poorly defined. This project will use cutting edge techniques such as genome-wide CRISPR-Cas9 screening to identify the pathways that ZUP1 functions in and how this promotes the cellular response to DNA damage.

This research fits within the mechanistic molecular and cellular bioscience framework of the DTP and explores how cells are regulated by post-translational modification.