These studies led his laboratory to discover the SCF complex SCFCdc4, which is the progenitor of what is now known to be a large family of ~250 enzymes known as cullin–RING ubiquitin ligases (CRLs) that are conserved throughout eukaryotes and exert a major impact on the regulation of numerous cellular and organismal processes. In parallel, they established the paradigm of phosphorylation-dependent targeting of SCF substrates. His lab went on to discover the critical catalytic subunit of SCFCdc4 (known as Rbx1/Roc1/Hrt1) and describe its mechanism of action. Subsequent studies identified key aspects of CRL mechanism of action. Particularly notable were their discoveries relating to the CRL regulators COP9 signalosome (CSN) and CAND1. In 2001-2002, the Deshaies lab showed that CSN, together with proteasome subunit Rpn11/PSMD14, are the founding members of a novel family of deubiquitinating enzymes. CSN plays a key role in regulating SCF and other CRL enzymes by removing the ubiquitin-like protein NEDD8 from their cullin subunit. In 2013, they showed that Cand1 has the unusual property of being a ‘protein exchange catalyst’ that equilibrates F-box subunits of SCF ubiquitin ligases with the cullin scaffold subunit. Proteasome: The Deshaies group pioneered the use of affinity purification to rapidly purify and characterize the composition of eukaryotic proteasomes, leading to the discovery of a large number of factors, including Rpn13 and Ubp6, that interact with the proteasome in yeast cells. In subsequent work they discovered that the Rpn11 subunit mediates removal of polyubiquitin chains from proteasome substrates as they are being degraded. P97/VCP: Early studies on p97 by the Deshaies group revealed a proteomic interaction network that includes all known UBX domain proteins, as well as a large number of ubiquitin ligase enzymes, including multiple CRLs. These findings indicated that the biological roles of p97 were far broader than was thought at the time. This was followed by identifying novel functions for p97, including removal of proteins from chromatin as part of the DNA damage response and extraction of stalled, nascent polypeptides from the ribosome. Drug development: Deshaies, in collaboration with Craig Crews (Yale), conceived the idea of using heterobifunctional small molecules, referred to as PROTACs, to tether cellular proteins to a ubiquitin ligase, resulting in ubiquitination and degradation of the tethered protein. This concept underlaid the launch of the biotechnology companies Arvinas, C4 Therapeutics, Kymera, Oncopia, and Cullgen. The Deshaies group also identified small molecules that inhibit targeting of substrates to