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Molecular genetics of maltose fermentation in the Saccharomyces yeasts

The Saccharomyces MAL loci. During most of her career, Dr. Michels used Saccharomyces yeasts to study the regulation of transcription in response to environmental changes. Her yeast genetics research initiated while a postdoctoral student with Julius Marmur in the Biochemistry Department of Albert Einstein College of Medicine, Bronx, NY and continued after joining the faculty of the Queens College Biology Department. During these years, Saccharomyces transitioned from a classical genetic organism to a molecular genetic model. After her sabbatical year with the Cold Spring Harbor yeast group, Dr. Michels focused on the MAL locus, a cluster of three genes needed to utilize the sugar maltose for energy (also called fermentation), using molecular genetic tools. In fact, these are the genes needed for producing beer and making bread rise. She chose to work on the MAL genes because the biochemistry of maltose utilization is very straightforward and the Saccharomyces response to the presence of maltose initially appeared to be a simple on-off switch. During the course of this research, Dr. Michels and her research team uncovered several unexpected and novel findings that lead to investigations in fields of cell biology and evolution that she would never have anticipated. The publications are listed below with links to pdf copies. The names of Dr. Michels' doctoral student are underlined.

Publications
Mitochondrial petite mutations
Saccharomyces is a facultative anaerobe capable of utilizing sugars in the absence and presence of oxygen. Additionally, a functional mitochondrion is not essential for growth on glucose. Mitochondrial DNA mutations are petite, that is, they form small white colonies compared to the normal grande colonies. Petites frequently carry deletions of some or all of the mtDNA. 

Michels, C.A., J. Blamire, B. Goldfinger and J. Marmur, 1975.  A genetic and biochemical analysis of the petite mutation in yeast.  Jour. Mol. Biol. 90: 431-449.

Blamire, J., C.A. Michels, J.M. Walsh and D.L. Friedenberg, 1976.  Mitochondrial DNA in yeast:  recombination and subsequent modification following mating between a grande and a suppressive petite.  Molec. Gen. Genet. 143: 253-259.

Glucose repression - early studies
Glucose repression (catabolite repression) is a global system controlling the expression of a wide variety of proteins in Saccharomyces. Among these, mitochondrial function is repressed and so-called mitochondrial ghosts form and complex sugars like sucrose and maltose are not fermented because their utilization enzymes are not expressed. Early analysis was carried out using classical genetic tools. The development of genetic engineering methods for Saccharomyces, was a game changer for studies of glucose repression.

Furst, A. and C.A. Michels, 1977.  D-glucosamine as a gratuitous catabolite repressor in yeast.  Molec. Gen. Genet. 155: 309-314.

Michels, C.A. and A. Romanowski, 1980.  Pleiotropic glucose repression-resistant mutations in Saccharomyces carlsbergensis. Jour. Bacteriol. 143: 674-679.

Mishra, S.D. and C.A. Michels, 1982.  Glucosamine-resistant mutations in yeast affecting the glucose repression sensitivity of electron transport enzymes.  Curr. Genet.  6: 209-217.

Michels, C.A., K.M. Hahnenberger and Y. Sylvestre, 1983.  Pleiotropic mutations regulating resistance to glucose repression in Saccharomyces carlsbergensis are allelic to the structural gene for hexokinase B.  Jour. Bacteriol. 153: 574-578.

Structure of the telomere-associated complex MAL loci
In collaboration with Richard Needleman, of the Wayne State University Biochemistry Department, Dr. Michels and her team isolated the Saccharomyces MAL6 locus. The showed that all Saccharomyces strains carry 1 to 5 telomere-proximal copies of a highly sequence homologous MAL locus. The basic structure of each MAL locus was characterized. The functions of each gene identified to be one positive regulatory gene, the MAL-activator, and two structural genes encoding maltose permease and maltase.  

Needleman, R.B. and C.A. Michels, 1983.  A repeated family of genes controlling maltose fermentation in Saccharomyces carlsbergensis.  Molec. Cell. Biol. 3: 796-802. pdf

Michels, C.A. and R.B. Needleman, 1983.  A genetic and physical analysis of the MAL1 and MAL3 standard strains of Saccharomyces cerevisiae.  Molec. Gen. Genet.  191: 225-230.

Michels, C.A. and R.B. Needleman, 1984.  The MAL loci:  A dispersed repeated family of loci in the Saccharomyces yeasts.  Jour. Bacteriol. 157: 949-952. pdf

Needleman, R.B., D.B. Kaback, R.A. Dubin, E.L. Perkins, N.G. Rosenberg, K.A. Sutherland, D.B. Forrest, and C.A. Michels, 1984.  MAL6 of Saccharomyces:  A complex locus containing three genes required for maltose fermentation.  Proc. Nat. Acad. Sci. USA 81: 2811-2815. pdf

Dubin, R.A., R.B. Needleman, D. Gosset, and C.A. Michels, 1985.  Identification of the structural gene encoding maltase within the MAL6 locus of Saccharomyces carlsbergensis.  Jour. Bacteriol. 164: 605-610. pdf

Charron, M.J., R.A. Dubin, and C.A. Michels, 1986.  Structural and functional analysis of the MAL1 locus of Saccharomyces cerevisiae.  Molec. Cell. Biol. 6: 3891-3899. pdf

Charron, M.J. and C.A. Michels, 1988.  The naturally occurring alleles of MAL1 in Saccharomyces species evolved by various mutagenic processes including chromosomal rearrangement.  Genetics 120: 83-93. pdf

Charron, M.J., E. Read, S.R. Haut, and C.A. Michels, 1989.  Molecular evolution of the telomere-associated MAL loci of Saccharomyces.  Genetics 122: 307-316. pdf

Cheng, Q. and C.A. Michels, 1989.  The maltose permease encoded by the MAL61 gene of Saccharomyces cerevisiae exhibits both sequence and structural homology to other sugar transporters.  Genetics 123: 477-484. pdf

Chang, Y. S., R.A. Dubin, E. Perkins, C.A. Michels, and R.B. Needleman, 1989.  Identification and characterization of the maltose permease in a genetically defined strain of Saccharomyces.  Jour. Bacteriol. 171: 6148-6154. pdf

Cheng, Q. and  C.A. Michels, 1991.  MAL11 and MAL61 encode the inducible, high-affinity maltose transporter of Saccharomyces cerevisiae.  Jour. Bacteriol. 173: 1817-1820. pdf

Naumova, E.S., G.I. Naumov, C.A. Michels, and D.R. Beritashvili, 1991.  Chromosomal DNA identification in yeast Saccharomyces bayanus and S. pastorianus.  Doklady Biological Sciences 316: 744-746. 

Naumov, G.I., E.S. Naumova, and C.A. Michels, 1991.  Identification of a functional a-glucosidase gene in natural mutants of Saccharomyces cerevisiae and S. paradoxus that do not ferment maltose.  Doklady Biological Sciences 316: 1249-1252.

Michels, C.A., E. Read, K. Nat and M.J. Charron, 1992.  The telomere-associated MAL3 locus of Saccharomyces is a tandem array of repeated genes.  Yeast 8: 655-665.

Naumov, G.I, E.S. Naumova, and C.A. Michels, 1994.  Genetic variation of the repeated MAL loci in natural populations of Saccharomyces cerevisiae and Saccharomyces paradoxus.  Genetics 136: 803-812. pdf

Han, E.-K., F. Cotty, C. Sottas, H. Jiang and C.A. Michels, 1995.  Characterization of AGT1 encoding a general  -glucoside transporter from Saccharomyces.  Molec. Microbiol. 17: 1093-1107. pdf

Regulation of MAL gene expression
The structural genes produce their products only in the presence of the inducer maltose. Dr. Michels' second goal was to understand, at the molecular and cellular, how Saccharomyces senses the presence of maltose and what events are needed to turn on the genes. The regulation of gene expression is fundamental to embryological development in multi-celled organisms and inappropriate gene expression is a basic cause of cancer. Thus, understanding how genes are regulated is one of the most fundamental questions of biology.  

Dubin, R.A., E.L. Perkins, R B. Needleman, and C.A. Michels, 1986.  Identification of a second trans-acting gene controlling maltose fermentation in Saccharomyces carlsbergenesis.  Molec. Cell. Biol. 6: 2757-2765. pdf

Charron, M.J. and C.A. Michels, 1987.  The constitutive, glucose-repression insensitive mutation of the yeast MAL4 locus is an alteration of the MAL43 gene.  Genetics 116: 23-31. pdf

Chang, Y.S., R.A. Dubin, E. Perkins, D. Forrest, C.A. Michels, and R.B. Needleman, 1988.  MAL63 codes for a positive regulator of maltose fermentation in Saccharomyces cerevisiae.  Curr. Genet. 114: 201-209.

Dubin, R.A., M.J. Charron, S.R. Haut, R.B. Needleman, and C.A.  Michels, 1988.  Constitutive expression of the maltose fermentative enzymes in Saccharomyces carlsbergensis is dependent upon the mutational activation of a nonessential homolog of MAL63.  Molec. Cell. Biol. 8: 1027-1035. pdf

Kim, J. and C.A. Michels, 1988.  The MAL63 gene of Saccharomyces encodes a cysteine-zinc finger protein.  Curr. Genet. 114: 319-323. 

Levine, J., L. Tanouye, and C.A. Michels, 1992.  The UAS-MAL is a bidirectional promotor element required for the expression of both the MAL61 and MAL62 genes of the Saccharomyces MAL6 locus.  Curr. Genet. 22: 181-189. 

Hu, Z., J.O. Nehlin, H. Ronne, and C.A. Michels, 1995. MIG1-dependent and MIG1-independent glucose regulation of MAL gene eaxpression in Saccharomyces cerevisiae.  Curr. Genet. 28: 258-266. 

Gibson, A.W., L. A. Wojciechowicz, S. E. Danzi, B. Zhang, J. Kim, Z. Hu, and C.A. Michels, 1997. Constitutive mutations of the Saccharomyces cerevisiae  MAL-activator genes MAL23, MAL43, MAL63, and mal64.  Genetics 146: 1287-1298. pdf

Hu, Z.,  A.W. Gibson,  J.H. Kim, L.A. Wojciechowicz, B. Zhang, and C.A. Michels, 1999. Functional domain analysis of the Saccharomyces MAL-activator. Curr. Genet. 36: 1-12. pdf

Hu, Z., Y. Yue, H. Jiang, B. Zhang, P.W. Sherwood, and C.A. Michels, 2000. Analysis of the mechanism by which glucose inhibits maltose induction of MAL gene expression in Saccharomyces. Genetics 154: 121-132. pdf

Danzi, S.E., B. Zhang, and C.A. Michels, 2000.  Alterations in the Saccharomyces MAL-activator cause constitutivity but can be suppressed by intragenic mutations. Curr. Genet. 38: 233-240. pdf

Wang, X., M. Bali, I. Medintz, and C.A. Michels, 2002. Intracellular maltose is sufficient to induce MAL gene expression in Saccharomyces cerevisiae. Eukaryotic Cell 1: 696-703. pdf

Danzi, S.E., M. Bali, and C.A. Michels, 2003. Clustered-charge to alanine-scanning mutagenesis of the Mal63 MAL-activator C-terminal regulatory domain. Curr. Genet. 44: 173-183. pdf

Bali, M., B. Zhang, K.A. Morano, and C.A. Michels, 2003. The Hsp90 molecular chaperone complex regulates maltose induction and stability of the Saccharomyces MAL gene transcription activator Mal63p. J. Biol. Chem. 278: 47441-47448. pdf 

Wang, X. and C.A. Michels, 2004. Mutations in SIN4 and RGR1 cause constitutive expression of MAL structural genes in Saccharomyces cerevisiae. Genetics 168: 747-757. pdf 

Ran, F., M. Bali, and C.A. Michels, 2008. Hsp90/Hsp70 chaperone machine regulation of the Saccharomyces MAL-activator as determined in vivo using noninducible and constitutive mutant alleles. Genetics 179:331-43. pdf

Ran, F., N. Gadura, and C.A. Michels, 2010. The Hsp90 cochaperone Aha1 is a negative regulator of the Saccharomyces MAL-activator and acts early in the chaperone cycle. Journ. Biol. Chem. 285: 13850-13862. pdf

Glucose repression of maltose permease

Medintz, I., H. Jiang, E.-K. Han, W. Cui, and C.A. Michels,1996. Characterization of the glucose-induced inactivation of maltose permease in Saccharomyces cerevisiae.  J. Bacteriol. 178: 2245-2254. pdf

Jiang, H., I. Medintz, and C.A. Michels, 1997.  Two glucose sensing/signalling pathways stimulate glucose-induced inactivation of maltose permease in Saccharomyces. Molec. Biol. Cell 8: 1293-1304. pdf

Medintz, I., H. Jiang, and C.A. Michels, 1998.  The role of ubiquitin-conjugation in glucose-induced proteolysis of Saccharomyces maltose permease.  Jour. Biol. Chem. 273: 34454-34462. pdf

Jiang, H., I. Medintz, P.W. Sherwood, and C.A. Michels, 2000. Metabolic signals trigger glucose-induced inactivation of maltose permease in Saccharomyces. J. Bacteriol.182: 647-654. pdf

Medintz, I., X. Wang, T. Hradek, and C.A. Michels, 2000. A PEST-like sequence in the N-terminal cytoplasmic domain of Saccharomyces maltose permease is required for glucose-induced proteolysis and rapid inactivation of transport activity. Biochemistry 39: 4518-4526. pdf

Jiang, H., K. Tatchell, S. Liu, and C.A. Michels, 2000. Protein phosphatase type-1 regulators REG1 and REG2 play a role in glucose-induced proteolysis of maltose permease in Saccharomyces. Molec. Gen. Genet. 263: 411-422. pdf

Gadura, N., L.C. Robinson, and C.A. Michels, 2006. Yck1,2 casein kinase type-1 signals to Glc7-Reg1 protein phosphatase to regulate the transport activity and glucose-induced inactivation of Saccharomyces maltose permease. Genetics 170: 1427-1439. pdf

Gadura, N. and C.A. Michels, 2006. Sequences in the N-terminal cytoplasmic domain of Saccharomyces cerevisiae maltose permease are required for vacuolar degradation but not glucose-induced internalization. Curr. Genet. 50: 101-14. pdf



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  • Research
    • Yeast
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    • Usher Syndrome
  • Open Science Forum
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    • Open Science Blog with Dr. Corinne Michels, PhD
    • Understanding Science
  • My paintings
    • Still Life paintings
    • Plein Air paintings
  • My garden