Every cell in our bodies receives signals which tell it whether to grow and divide, to differentiate into a specific cell type (e.g. a muscle cell or a neuron) or even to commit suicide. These signals are transmitted by classes of proteins, known as enzymes, which modify other proteins. These modified proteins are in turn recognized by specialized proteins to dictate the proper cellular response. A key regulatory system in the cell utilizes a chemical group called "acetyl" for the modifications and the response to signals. In many cancers, the enzymes responsible for the addition of the acetyl modification and the proteins that recognize this modification are mutated. Drugs that target the process of acetyl modification and recognition are being developed and are showing great promise in the clinic to treat diverse cancers. Yet, despite this fact, there is very little known regarding how specificity is acquired in this acetyl modification pathway. For example, there are 42 distinct proteins that are able to recognize the acetyl modification. Similar to a lock and key mechanism, these proteins need to recognize the acetyl modification only in the context of specific proteins, but what these proteins are is unclear at the moment. The co-applicants have established a strong expertise in the use of an approach called mass spectrometry, which essentially identifies proteins using a unique "fingerprint" that each protein produces, and structural biology, which allows them to "see" how the lock and key mechanism functions. By combining these techniques with molecular and cell biology approaches, the applicants will determine how the acetyl modification system is organized. They will also test newly designed drugs that target the acetyl modification system to assess in a timely fashion which of the new drugs hold potential as therapeutic agents.