Carter-O'Connell Lab - Research Focus

Research in the Carter-O'Connell Lab

The Carter-O'Connell lab sits at the interface of chemistry, biochemistry, molecular, cellular, and systems biology. Our lab leverages methodologies from these varied disciplines to uncover the role of ADP-ribosylation (ADPr) signaling networks within the cell. ADPr has emerged as an essential posttranslational protein modification (PTM) implicated in a wide-array of biological functions and multiple disease states, including cancer. In humans, ADP-ribose transfer is catalyzed by a series of 17 enzymes known as poly-ADP-ribose polymerases (PARPs). The PARP enzymes transfer ADP-ribose from nicotinamide adenine dinucleotide (NAD+) onto target proteins. PARP enzymes can also be divided between those that polymerize chains of poly-ADP-ribose (poly-PARPs) and those that can only add a single mono-ADP-ribose (mono-PARPs). The addition of ADP-ribose alters the charge state of the protein and can affect protein binding, activity, and stability. PARP1, a poly-PARP, has received the bulk of scientific scrutiny due to its role in single-strand base repair and the efficacy of targeting PARP1 activity in certain cancers. However, the majority of the PARPs have remained poorly understood due to a lack of tools to identify their targets in the cell.

As the PARP field rapidly evolves, we are focusing on breaking down the specific roles for each of the PARP family-members within the cell. We start by building a systems level view of the individual targets for each specific PARP isoform. Work pioneered with our collaborators in the Cohen lab at OHSU allowed us to utilize a chemical genetics strategy to create a large dataset of selective PARP protein targets. From this broad, top-down view we are delving deeply into the molecular mechanisms by which each PARP enzyme modulates its specific protein targeting, effects cellular signal transduction, and contributes to different disease states. We view this dialogue between a systems-level and a biochemical perspective as iterative, enhancing our understanding of PARP-dependent biology.