Alexander Varshavsky

Alexander J. Varshavsky (Russian: Александр Яковлевич Варшавский; born 1946 in Moscow) is a Russian American biochemist and geneticist. He works at the California Institute of Technology (Caltech) as the Morgan Professor of Biology. Varshavsky left Russia in 1977, emigrating to United States. 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. His current research continues to focus on the ubiquitin system and N degron pathways.

Varshavsky received a B. S. degree from the Moscow University (Russia) (1970) and Ph. D. from the Institute of Molecular Biology, Moscow, Russia (1973). 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). From 1992 to 2016, he worked as the Howard Smits Professor of Cell Biology at the Division of Biology and Biological Engineering, California Institute of Technology (Caltech), in Pasadena, CA. Since 2017, he is the Thomas Hunt Morgan Professor of Biology at Caltech.

Varshavsky is a Fellow of the American Academy of Arts and Sciences (1987), a Member of the U. S. National Academy of Sciences (1995), a Fellow of the American Academy of Microbiology (2000), a Member of the American Philosophical Society (2001), a Fellow of the American Association for the Advancement of Science (2002), a Foreign Associate of the European Molecular Biology Organization (2001), and a Foreign Member of the European Academy of Sciences (Academia Europaea) (2005).

Varshavsky received the Merit Award from the National Institutes of Health (1998), the Novartis Drew Award in Biomedical Sciences (1998), the Gairdner International Award (Canada, 1999), the Sloan Prize in Cancer Research (2000), the Albert Lasker Award in Basic Medical Research (2000), the Shubitz Prize in Cancer Research (2000), the Hoppe Seyler Award (Germany, 2000), the Pasarow Award in Cancer Research (2001), the Wolf Prize in Medicine (Israel, 2001), the Max Planck Award (Germany, 2001), the Massry Prize (2001), the Merck Award (2001), the Horwitz Prize (2002), the Wilson Medal (2004), the Stein and Moore Award (2005), the March of Dimes Prize in Developmental Biology (2006), the Griffuel Prize in Cancer Research (France, 2006), the Gagna and Van Heck Prize (Belgium, 2006), the Weinstein Award in Cancer Research (2007), the Schleiden Medal (Germany, 2007), the Gotham Prize in Cancer Research (2008), the Vilcek Prize in Biomedical Sciences (2010), the BBVA Award in Biomedicine (Spain, 2001), the Otto Warburg Prize (Germany, 2012), the King Faisal Prize in Science (Saudi Arabia, 2012), the Breakthrough Prize in Life Sciences (2014), the Albany Prize in Medicine (2014), the Grande Médaille of the French Academy of Sciences (France, 2016), the Wieland Prize (Germany, 2017), the IUBMB Medal from the International Union of Biochemistry and Molecular Biology (2019), the Debrecen Award in Molecular Medicine (Hungary, 2022), the Hope Award in Basic Science (2023), and the Hogg Award in Cancer Research (2023). “Degron”, by now a standard term, was introduced by Varshavsky in 1991. During 1984 1990, the Varshavsky lab discovered biological fundamentals of the ubiquitin system. 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. ). The other two sets (items 2 and 3 below) were discovered by the Varshavsky laboratory, then at the Massachusetts Institute of Technology (Cambridge, Massachusetts). and references therein).

1. The discovery, in 1978 1979, of the first nucleosome depleted, nuclease hypersensitive regions in chromosomes. Such “exposed” chromosomal segments are characteristic of transcriptional promoters, recombination hotspots, and the origins of DNA replication. 4. A verifiable conjecture about molecular basis of sleep causation, termed the fragment generation (FG) hypothesis. 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 FG hypothesis is consistent with available experimental evidence. It remains to be verified. 5. Inventions of genetic and biochemical methods (1980 2017) (see references and references therein):

(i) A method for two dimensional electrophoretic mapping of DNA replication/multicatenation intermediates, in 1980 1981. (ii) Nucleosome mapping using a two dimensional hybridization method, in 1982. (iii) The ubiquitin fusion technique, in 1986. This method makes it possible to expose, in vivo, a desired N terminal residue in a protein of interest. Owing to the mechanics of the genetic code, all nascent proteins bear the N terminal Met residue, which is either retained in or removed from mature proteins. The ubiquitin fusion technique makes it possible to “bypass” the endogenous rules of N terminal Met removal and retention. (iv) Chromatin immunoprecipitation (ChIP) assay, in 1988. Advanced versions of ChIP are being used for mapping in vivo locations of chromosomal proteins. (v) Mutations in many (most) genes that cause a hypersensitivity to heavy water (D2O), a novel and generally applicable conditional phenotype, in 1988. (vi) Heat activated N degron for producing temperature sensitive mutants, in 1994. (vii) Split ubiquitin method for detecting protein interactions in vivo, in 1994. The central idea of the split ubiquitin technique opened the field of single subunit split proteins, such as split GFP, split lactamase, split Cas9 CRISPR nuclease, and many other split protein sensors and effectors. (viii) Ubiquitin translocation assay, in 1994, for analyzing, in vivo, specific mechanisms and kinetics of protein translocation across cellular membranes. (ix) Ubiquitin sandwich technique, in 2000. It uses ubiquitin fusions and multiple tandem reporters to detect and measure cotranslational proteolysis in vivo. (x) Subunit decoy technique, in 2013, for analyzing the in vivo regulation of subunit stoichiometries in oligomeric proteins. (xi) Promoter reference technique, in 2017. 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. 1. Alexander Varshavsky, California Institute of Technology (Caltech) (https://www. bbe. caltech. edu/people/alexander varshavsky). 2. Varshavsky, A. "(2022) Interview about life and work, to David Zierler, Caltech Heritage Project" (https://heritageproject. caltech. edu/interviews updates/alexander varshavsky). 3. Bachmair, A.,Finley, D., Varshavsky, A. (1986)) In vivo half life of a protein is a function of Its N terminal residue. Science 234: 179–186. doi:10.1126/science.3018930. 4. Varshavsky, A. (2008) Discovery of cellular regulation by protein degradation. Journal of Biological Chemistry 283: 34469 34489. doi:10.1074/jbc. x800009200. 5. Varshavsky, A. (2019)) N degron and C degron pathways of protein degradation. Proceedings of the National Academy of Sciences 116 : 358–366. doi:10.1073/pnas.1816596116. 6. Jentsch, S., McGrath, J. P., Varshavsky, A. (1987) The yeast DNA repair gene RAD6 encodes a ubiquitin conjugating enzyme. Nature 329: 131 134. doi:10.1038/329131a0. 7. Johnson, E. S., Gonda, D. K., Varshavsky, A. (1990) Cis trans recognition and subunit specific degradation of short lived proteins. Nature 346: 287 291. doi:10.1038/346287a0. 8. Varshavsky, A. (2014). "Discovery of the biology of the ubiquitin system". Journal of the American Medical Association (JAMA) 311: 1969. doi:10.1001/jama.2014.5549. 9. Hershko, A. Ciechanover, A., Varshavsky, A. (2000) The ubiquitin system. Nature Medicine 6: 1073 1081. doi:10.1038/80384. 10. Oh, J. H., Hyun, J. Y.,  Chen, S. J., Varshavsky, A. (2020) "Five enzymes of the Arg/N degron pathway form a targeting complex: the concept of superchanneling". Proceedings of the National Academy of Sciences 117 (20): 10778 10788. doi:10.1073/pnas.2003043117. 11. Vu, T. T. M., Mitchell, D. C., Gygi, S. P., Varshavsky, A. (2020) "The Arg/N degron pathway targets transcription factors and regulates specific genes". Proceedings of the National Academy of Sciences 117: 31094 31104. 12. Varshavsky, A. (2007) Targeting the absence: homozygous DNA deletions as immutable signposts for cancer therapy. Proceedings of the National Academy of Sciences 104: 14935 14940. doi:10.1073/pnas.0706546104. 13. Varshavsky, A., Lewis, K., Chen, S. J. (2023). Deletions of DNA in cancer and their possible uses for therapy. BioEssays 45. doi:10.1002/bies.202300051. 14. Varshavsky, A. (2019) On the cause of sleep: protein fragments, the concept of sentinels, and links to epilepsy. Proceedings of the National Academy of Sciences 116: 10773 10782. doi:10.1073/pnas.1904709116.