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Alexander Varshavsky

January 01, 1970

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.

Varshavsky (in 2007)

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.

Education and appointments edit

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.[1]

Honorary memberships edit

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).[1][2]

Awards edit

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).[1][2]

Contributions in the ubiquitin field edit

In 1986, the Varshavsky laboratory discovered and analyzed the first degradation signals (degrons) in short-lived proteins.[3][4][5] “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.[3][4][5][6][7][8] 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. [9]).The other two sets (items 2 and 3 below) were discovered by the Varshavsky laboratory, then at the Massachusetts Institute of Technology (Cambridge, Massachusetts).[3][4][5][6][7][8]

(1) A. Ciechanover and A. Hershko demonstrated that ubiquitin, a 76-residue protein, is covalently conjugated to other proteins in cell extracts, a novel protein modification involved in the ATP-dependent protein degradation in extracts from mammalian reticulocytes (reviewed in ref. [9]).Ubiquitylation of a test protein in a reticulocyte extract caused it to become short-lived in the extract. Hershko, Ciechanover, Rose and their colleagues also discovered that ubiquitin-protein conjugation is mediated by a cascade of enzymes, termed E1, E2 and E3. These studies were carried out using cell-free (in vitro) extracts and isolated E1-E3 enzymes.[9] 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.[3][4][5][6][7][8] N-terminal degrons, called N-degrons, were the first degradation signals to be discovered. Ubiquitin-dependent proteolytic systems that selectively destroy proteins bearing N-degrons are called N-degron pathways. Prior to 2019, these systems were called N-end rule pathways.[3][4][5]

(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.[3][4][5][6][7][8] 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).[3][4][5][6][7][8] In addition, the Varshavsky lab identified the MATalpha2 transcriptional repressor as the first physiological substrate of the ubiquitin system (in 1990), cloned the first genes encoding ubiquitin precursors (in 1984-1989), identified the first ubiquitin-conjugating (E2) enzymes with specific biological functions (in 1987-1988), discovered a nonproteolytic function of ubiquitin (its activity as a cotranslational chaperone) (in 1989), cloned the first deubiquitylating enzymes, termed UBP1-UBP3, and cloned the first specific E3 ubiquitin ligase, termed UBR1 (in 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. This multitude of E3s underlies the enormous functional range of the ubiquitin system. In addition, the Varshavsky lab discovered, in 1989, the first specific substrate-linked polyubiquitin chains, and demonstrated, in 1990, the subunit selectivity of degradation of oligomeric proteins by the ubiquitin system (references [3][4][5][6][7][8] and references therein).

In sum, the complementary discoveries by the laboratories of Hershko and Varshavsky during the 1980s (items 1-3 above) yielded the modern paradigm of the central importance of protein degradation for the regulation of most proteins in vivo, on a par with the control by transcription and translation. 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.[4][5][8][9]

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 [4][5][8][9][10][11][12] and references therein).

Contributions outside the ubiquitin field edit

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.[2][4]

2. The discovery, in 1980-1981, of the first pathway of chromosome cohesion/segregation. It involves the formation, during DNA replication, of multiply intertwined (multicatenated) sister chromatids, and their later stepwise decatenation by type-2 DNA topoisomerases.[2][4]

3. The idea, in 2007, that DNA deletions (and less frequent insertions) that are characteristic of cancer cells can be used as non-reverting cancer-specific signposts, thereby making possible a selective therapy of cancers that would be impervious to tumor progression.[12][13]

4. A verifiable conjecture about molecular basis of sleep causation, termed the fragment generation (FG) hypothesis.[14] 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.[14]

5. Inventions of genetic and biochemical methods (1980-2017) (see references [2][4][8] 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. doi:10.1073/pnas.2020124117

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.

References edit

  1. ^ a b c "Alexander Varshavsky, California Institute of Technology (Caltech)". www.bbe.caltech.edu. Retrieved 2023-12-11.
  2. ^ a b c d e "Alexander Varshavsky, Biochemist and Geneticist". Heritage Project. 2022-07-11. Retrieved 2023-12-11.
  3. ^ a b c d e f g h Bachmair, A.; Finley, D.; Varshavsky, A. (1986). "In vivo half-life of a protein is a function of Its N-terminal residue". Science. 234 (4773): 179–186. doi:10.1126/science.3018930. PMID 3018930.
  4. ^ a b c d e f g h i j k l m Varshavsky, A. (2008). "Discovery of cellular regulation by protein degradation". Journal of Biological Chemistry. 283 (50): 34469–34489. doi:10.1074/jbc.X800009200. PMC 3259866. PMID 18708349.
  5. ^ a b c d e f g h i j Varshavsky, A. (2019). "N-degron and C-degron pathways of protein degradation". Proceedings of the National Academy of Sciences. 116 (2): 358–366. Bibcode:2019PNAS..116..358V. doi:10.1073/pnas.1816596116. PMC 6329975. PMID 30622213.
  6. ^ a b c d e f Jentsch, S.; McGrath, J. P.; Varshavsky, A. (1987). "The yeast DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme". Nature. 329 (6135): 131–134. Bibcode:1987Natur.329..131J. doi:10.1038/329131a0. S2CID 4317877.
  7. ^ a b c d e f Johnson, E. S.; Gonda, D. K.; Varshavsky, A. (1990). "Cis-trans recognition and subunit-specific degradation of short-lived proteins". Nature. 346 (6281): 287–291. Bibcode:1990Natur.346..287J. doi:10.1038/346287a0. PMID 2165217. S2CID 4321710.
  8. ^ a b c d e f g h i Varshavsky, A. (2014). "Discovery of the biology of the ubiquitin system". JAMA. 311 (19): 1969. doi:10.1001/jama.2014.5549. PMID 24846030.
  9. ^ a b c d e Hershko, A.; Ciechanover, A.; Varshavsky, A. (2000). "The ubiquitin system". Nature Medicine. 6 (10): 1073–1081. doi:10.1038/80384. PMID 11017125. S2CID 25244378.
  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. Bibcode:2020PNAS..11710778O. doi:10.1073/pnas.2003043117. PMC 7245096. PMID 32366662.
  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 (49): 31094–31104. Bibcode:2020PNAS..11731094V. doi:10.1073/pnas.2020124117. PMC 7733807.
  12. ^ a b Varshavsky, A. (2007). "Targeting the absence: homozygous DNA deletions as immutable signposts for cancer therapy". Proceedings of the National Academy of Sciences. 104 (38): 14935–14940. doi:10.1073/pnas.0706546104. PMC 1986591. PMID 17846424.
  13. ^ Varshavsky, A.; Lewis, K.; Chen, S. J. (2023). "Deletions of DNA in cancer and their possible uses for therapy". BioEssays. 45 (7): e2300051. doi:10.1002/bies.202300051. PMID 37166062. S2CID 258617479.
  14. ^ a b 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 (22): 10773–10782. Bibcode:2019PNAS..11610773V. doi:10.1073/pnas.1904709116. PMC 6561186. PMID 31085645.

Notes edit

January 01, 1970
alexander, varshavsky, alexander, varshavsky, russian, Александр, Яковлевич, Варшавский, born, 1946, moscow, russian, american, biochemist, geneticist, works, california, institute, technology, caltech, morgan, professor, biology, varshavsky, left, russia, 197. Alexander J Varshavsky Russian Aleksandr Yakovlevich Varshavskij 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 Varshavsky in 2007 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 Contents 1 Education and appointments 2 Honorary memberships 3 Awards 4 Contributions in the ubiquitin field 5 Contributions outside the ubiquitin field 6 References 7 NotesEducation and appointments editVarshavsky 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 1 Honorary memberships editVarshavsky 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 1 2 Awards editVarshavsky 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 Medaille 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 1 2 Contributions in the ubiquitin field editIn 1986 the Varshavsky laboratory discovered and analyzed the first degradation signals degrons in short lived proteins 3 4 5 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 3 4 5 6 7 8 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 9 The other two sets items 2 and 3 below were discovered by the Varshavsky laboratory then at the Massachusetts Institute of Technology Cambridge Massachusetts 3 4 5 6 7 8 1 A Ciechanover and A Hershko demonstrated that ubiquitin a 76 residue protein is covalently conjugated to other proteins in cell extracts a novel protein modification involved in the ATP dependent protein degradation in extracts from mammalian reticulocytes reviewed in ref 9 Ubiquitylation of a test protein in a reticulocyte extract caused it to become short lived in the extract Hershko Ciechanover Rose and their colleagues also discovered that ubiquitin protein conjugation is mediated by a cascade of enzymes termed E1 E2 and E3 These studies were carried out using cell free in vitro extracts and isolated E1 E3 enzymes 9 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 3 4 5 6 7 8 N terminal degrons called N degrons were the first degradation signals to be discovered Ubiquitin dependent proteolytic systems that selectively destroy proteins bearing N degrons are called N degron pathways Prior to 2019 these systems were called N end rule pathways 3 4 5 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 3 4 5 6 7 8 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 3 4 5 6 7 8 In addition the Varshavsky lab identified the MATalpha2 transcriptional repressor as the first physiological substrate of the ubiquitin system in 1990 cloned the first genes encoding ubiquitin precursors in 1984 1989 identified the first ubiquitin conjugating E2 enzymes with specific biological functions in 1987 1988 discovered a nonproteolytic function of ubiquitin its activity as a cotranslational chaperone in 1989 cloned the first deubiquitylating enzymes termed UBP1 UBP3 and cloned the first specific E3 ubiquitin ligase termed UBR1 in 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 This multitude of E3s underlies the enormous functional range of the ubiquitin system In addition the Varshavsky lab discovered in 1989 the first specific substrate linked polyubiquitin chains and demonstrated in 1990 the subunit selectivity of degradation of oligomeric proteins by the ubiquitin system references 3 4 5 6 7 8 and references therein In sum the complementary discoveries by the laboratories of Hershko and Varshavsky during the 1980s items 1 3 above yielded the modern paradigm of the central importance of protein degradation for the regulation of most proteins in vivo on a par with the control by transcription and translation 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 4 5 8 9 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 4 5 8 9 10 11 12 and references therein Contributions outside the ubiquitin field edit1 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 2 4 2 The discovery in 1980 1981 of the first pathway of chromosome cohesion segregation It involves the formation during DNA replication of multiply intertwined multicatenated sister chromatids and their later stepwise decatenation by type 2 DNA topoisomerases 2 4 3 The idea in 2007 that DNA deletions and less frequent insertions that are characteristic of cancer cells can be used as non reverting cancer specific signposts thereby making possible a selective therapy of cancers that would be impervious to tumor progression 12 13 4 A verifiable conjecture about molecular basis of sleep causation termed the fragment generation FG hypothesis 14 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 14 5 Inventions of genetic and biochemical methods 1980 2017 see references 2 4 8 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 doi 10 1073 pnas 202012411712 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 References edit a b c Alexander Varshavsky California Institute of Technology Caltech www bbe caltech edu Retrieved 2023 12 11 a b c d e Alexander Varshavsky Biochemist and Geneticist Heritage Project 2022 07 11 Retrieved 2023 12 11 a b c d e f g h Bachmair A Finley D Varshavsky A 1986 In vivo half life of a protein is a function of Its N terminal residue Science 234 4773 179 186 doi 10 1126 science 3018930 PMID 3018930 a b c d e f g h i j k l m Varshavsky A 2008 Discovery of cellular regulation by protein degradation Journal of Biological Chemistry 283 50 34469 34489 doi 10 1074 jbc X800009200 PMC 3259866 PMID 18708349 a b c d e f g h i j Varshavsky A 2019 N degron and C degron pathways of protein degradation Proceedings of the National Academy of Sciences 116 2 358 366 Bibcode 2019PNAS 116 358V doi 10 1073 pnas 1816596116 PMC 6329975 PMID 30622213 a b c d e f Jentsch S McGrath J P Varshavsky A 1987 The yeast DNA repair gene RAD6 encodes a ubiquitin conjugating enzyme Nature 329 6135 131 134 Bibcode 1987Natur 329 131J doi 10 1038 329131a0 S2CID 4317877 a b c d e f Johnson E S Gonda D K Varshavsky A 1990 Cis trans recognition and subunit specific degradation of short lived proteins Nature 346 6281 287 291 Bibcode 1990Natur 346 287J doi 10 1038 346287a0 PMID 2165217 S2CID 4321710 a b c d e f g h i Varshavsky A 2014 Discovery of the biology of the ubiquitin system JAMA 311 19 1969 doi 10 1001 jama 2014 5549 PMID 24846030 a b c d e Hershko A Ciechanover A Varshavsky A 2000 The ubiquitin system Nature Medicine 6 10 1073 1081 doi 10 1038 80384 PMID 11017125 S2CID 25244378 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 Bibcode 2020PNAS 11710778O doi 10 1073 pnas 2003043117 PMC 7245096 PMID 32366662 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 49 31094 31104 Bibcode 2020PNAS 11731094V doi 10 1073 pnas 2020124117 PMC 7733807 a b Varshavsky A 2007 Targeting the absence homozygous DNA deletions as immutable signposts for cancer therapy Proceedings of the National Academy of Sciences 104 38 14935 14940 doi 10 1073 pnas 0706546104 PMC 1986591 PMID 17846424 Varshavsky A Lewis K Chen S J 2023 Deletions of DNA in cancer and their possible uses for therapy BioEssays 45 7 e2300051 doi 10 1002 bies 202300051 PMID 37166062 S2CID 258617479 a b 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 22 10773 10782 Bibcode 2019PNAS 11610773V doi 10 1073 pnas 1904709116 PMC 6561186 PMID 31085645 Notes editCaltech bio The Gotham prize Retrieved from https en wikipedia org w index php title Alexander Varshavsky amp oldid 1206167462, wikipedia, wiki, book, books, library,

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