Alexander Varshavsky
Alexander J. Varshavsky (Russian: Александр Яковлевич Варшавский; born 1946 in Moscow) is a Russian-American biochemist and geneticist.
His laboratory, initially at the Massachusetts Institute of Technology, and later at Caltech, has discovered, during the 1980s, the first degradation signals (degrons) in short-lived proteins and biological fundamentals of the ubiquitin system.
From 1973-1977, he worked as a Junior Scientist at the Moscow’s Institute of Molecular Biology, before becoming a faculty member at MIT, Cambridge, MA, USA (1977-1991).
[1][2] Dr. Paul Janssen Award for Biomedical Research (2024)[3] In 1986, the Varshavsky laboratory discovered and analyzed the first degradation signals (degrons) in short-lived proteins.
[4][5][6][7][8][9] The field of ubiquitin and regulated protein degradation was created in the 1980s through complementary discoveries, during 1978-1990, that revealed three sets of previously unknown facts.
The first set of these facts (item 1 below) was discovered by the A. Hershko laboratory at the Technion (Haifa, Israel) (reviewed in ref.
Hershko, Ciechanover, Rose and their colleagues also discovered that ubiquitin-protein conjugation is mediated by a cascade of enzymes, termed E1, E2 and E3.
[10] At that time, in the early 1980s, physiological significance of the ubiquitin system and its specific biological functions remained unknown.
(2) In 1986, the in vivo selectivity of ubiquitylation (ubiquitin-protein conjugation) was shown, by the Varshavsky lab, to be determined by degradation signals (degrons) in cellular proteins.
[4][5][6] (3) During 1984-1990, the Varshavsky lab discovered that ubiquitylation has remarkably broad biological functions, to a large extent through control of the in vivo levels of cellular proteins.
[4][5][6][7][8][9] Varshavsky and coworkers demonstrated in 1984 that the bulk of protein degradation in living cells requires ubiquitylation.
Soon thereafter, they identified the first specific biological functions of ubiquitylation, including DNA repair (1987), the cell division cycle (1988), stress responses (1987), protein synthesis (1989), and transcriptional regulation (1990).
The latter advance opened a particularly large field, since later studies showed that the human genome encodes more than 600 distinct E3 ubiquitin ligases.
Given the exceptionally broad functional range of the ubiquitin system and numerous ways in which ubiquitin-dependent processes can malfunction in disease, from cancer and neurodegenerative syndromes to defects in immunity and other illnesses, including birth defects, the resulting change in our understanding of biological circuits has major implications for medicine.
[5][6][9][10] Varshavsky and coworkers continued their studies of the ubiquitin system in the ensuing decades (from 1990 to the present), focusing on N-degron pathways.
Wide-ranging functions of these pathways include the selective destruction of misfolded proteins, the sensing of specific compounds such as oxygen, heme, short peptides and nitric oxide, the regulation of DNA transcription, replication, repair, and chromosome cohesion/segregation, the control of peptide transport, meiosis, chaperones, cytoskeletal proteins, gluconeogenesis, autophagy, apoptosis, adaptive and innate immunity, cardiovascular development, neurogenesis, spermatogenesis, and circadian rhythms; diverse involvements in human diseases such as cancer, neurodegeneration, and perturbations of immunity; a variety of roles in bacteria; and many functions in plants, including seed germination and oxygen/NO sensing (references [5][6][9][10][11][12][13] and references therein).
Such “exposed” chromosomal segments are characteristic of transcriptional promoters, recombination hotspots, and the origins of DNA replication.
A verifiable conjecture about molecular basis of sleep causation, termed the fragment generation (FG) hypothesis.
[15] According to the FG hypothesis, a molecular cause of sleep stems from production, during wakefulness, of numerous extracellular and intracellular protein-sized protein fragments that can be transiently beneficial but can also perturb, through their diverse and cumulative effects, the functioning of the brain and other organs.
The FG hypothesis posits that sleep evolved, at least in part, to counteract overproduction (owing to an insufficiently fast elimination) of hundreds of different protein fragments during wakefulness.
The ubiquitin fusion technique makes it possible to “bypass” the endogenous rules of N-terminal Met removal and retention.
(v) Mutations in many (most) genes that cause a hypersensitivity to heavy water (D2O), a novel and generally applicable conditional phenotype, in 1988.
It uses ubiquitin fusions and multiple tandem reporters to detect and measure cotranslational proteolysis in vivo.
This reference-based method for measuring the in vivo protein degradation uses RNA aptamers and bypasses the necessity of global translation inhibitors in a chase-degradation assay.
"(2022) Interview about life and work, to David Zierler, Caltech Heritage Project".. (https://heritageproject.caltech.edu/interviews-updates/alexander-varshavsky).
