Alexander Varshavsky

Research by the laboratory of Alexander Varshavsky (at MIT from 1977 to 1992, and at the California Institute of Technology (Caltech) from 1992 to the present time) focuses on the ubiquitin-proteasome system, with an emphasis on the N-end pathways of protein degradation. (They were previously called “N-end rule pathways.”) In the 1980s, the Varshavsky laboratory discovered the first degradation signals (degrons) in short-lived protein as well as the fundamental biology of the ubiquitin system. These advances comprised the demonstration that ubiquitylation is essential for protein degradation in living cells (1984); the discovery of specific functions of ubiquitin conjugation (1987-1990), in the cell cycle, DNA repair, protein synthesis, stress responses, and transcriptional regulation; the discovery of the N-end rule pathway and thereby of the first degradation signals in short‑lived proteins (1986-1989); the discovery of substrate-linked polyubiquitin chains and their necessity for protein degradation (1989); the discovery of subunit selectivity of proteolysis (1990); the identification of the first physiological substrate of the ubiquitin system (MATalpha2) (1990); the discovery of the first nonproteolytic function of ubiquitin (1989); and the cloning of the first E3 ubiquitin ligase (1990). The latter advance opened up a particularly large field, as the human genome is now known to encode nearly 1,000 distinct E3 ubiquitin ligases. The targeting of cellular proteins by this multitude of E3 ubiquitin ligases underlies the immense functional reach of the ubiquitin system. The resulting overall discovery, by Varshavsky and coworkers, of the physiological regulation by intracellular protein degradation has transformed the understanding of biological circuits, as it became clear that control through regulated protein degradation rivals, and often surpasses in significance the classical regulation through transcription and translation. Other contributions by the Varshavsky laboratory include the discovery of the first exposed (nucleosome-depleted) regions in chromosomes (in 1978-1979); the discovery of the DNA multicatenane-based mechanism for chromosome cohesion/segregation (in 1980-1981); and the discovery of accelerated (stress-induced) gene amplification in mammalian cells (in 1981). In addition, his laboratory developed new biochemical and genetic methods, including the ubiquitin fusion technique (in 1986); the chromatin immunoprecipitation (ChIP) assay (in 1988), the hypersensitivity to heavy water as a general method for conditional mutagenesis (in 1988), the heat‑activated degron (in 1994), the split-ubiquitin assay for protein interactions (in 1994); the ubiquitin translocation assay (in 1994); the ubiquitin reference technique (URT) (in 1996); the ubiquitin sandwich technique (in 2000); the subunit decoy technique (in 2013); and the promoter reference technique (PRT) (in 2017).