Alexander Varshavsky

California Institute of Technology


Primary Section: 21, Biochemistry
Secondary Section: 22, Cellular and Developmental Biology
Membership Type: Member (elected 1995)

Research Interests

In 1984-1990, studies by my laboratory discovered the first degradation signals (N-degrons) in short-lived proteins; the singular biological significance of the ubiquitin system (until then, ubiquitin-dependent proteolysis was defined solely in cell-free in vitro systems); the first physiological functions of ubiquitylation, in the cell cycle, DNA repair, protein synthesis, transcriptional regulation, and stress responses; the Arg/N-degron pathway as the first specific pathway of the ubiquitin system; the subunit selectivity of ubiquitin-dependent proteolysis; the first specific polyubiquitin chains and their necessity for protein degradation; the MATalpha2 repressor as the first physiological substrate of the ubiquitin system; the first nonproteolytic function of ubiquitin (as a chaperone in the biogenesis of ribosomes); and initiated the molecular genetic understanding of the ubiquitin system, including the cloning of the first E3 ubiquitin ligase (Ubr1), the first deubiquitylases (Ubp1-Ubp3), and the first precursors of free ubiquitin (Ubi1-Ubi4). Just how broad and elaborate ubiquitin functions are was understood systematically over the next three decades, through studies by many laboratories that entered this field in the 1990s and afterward, an expansion that continues to this day. Our current studies focus on several N-degron pathways, discovered in 1986 and during the 2010s. Some of new methods developed by our lab: chromatin immunoprecipitation (ChIP) assay; ubiquitin fusion technique; ubiquitin reference technique; ubiquitin translocation technique; split-ubiquitin technique; ubiquitin sandwich technique, heat-inducible N-degron; subunit decoy technique; promoter reference degradation assay.

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