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Norbert Lehming

 
norbert-lehming.jpg

Associate Professor Norbert Lehming
Dr. rer. nat.
Principal Investigator
MMID2

Associate Professor
Department of Microbiology and Immunology
National University of Singapore

micln@nus.edu.sg

Biography

Dr. Norbert Lehming received his Staatsexamen in Biology and Chemistry from the University of Cologne in Germany. He stayed in the same city to pursue his graduate studies in the laboratory of Professor Benno Müller-Hill at the Institute for Genetics and obtained his Dr. rer. nat. from the University of Cologne in 1990.

Dr. Norbert Lehming performed his post-doctoral research in the laboratory of Professor Mark Ptashne at the Department of Biochemistry, Harvard University, USA. In 1995, he became an independent Group Leader at the Max-Planck-Institute for Genetics in Cologne and he received his Habilitation from the University of Cologne in 2000. Dr. Norbert Lehming joined the National University of Singapore as an Assistant Professor in 2001 and he became an Associate Professor in 2011.

Research Interests

The Regulation of Gene Expression

Together with Professors Alex Varshavsky and Nils Johnsson, Dr. Norbert Lehming has developed and patented the Split-Ubiquitin System to identify and study protein-protein interactions that are relevant for Transcription. Proteins of interest can be fused to the C-terminal half of ubiquitin that has been extended by the Ura3 enzyme, which carries an arginine as its first amino acid (RUra3). Libraries of proteins fused to the N-terminal half of ubiquitin can be screened for interacting partners of the proteins of interest. The protein-protein interactions bring the two halves of ubiquitin into close proximity, and the RUra3 enzyme is cleaved off the fusion and rapidly degraded by the enzymes of the N-end rule. RUra3 converts hamless fluoro-orotic acid (FOA) into toxic fluoro-uracil and interacting partners can be identified by their ability to confer growth on FOA plates. Dr. Norbert Lehming has used the Split-Ubiquitin System to isolate interacting partners for transcriptional activators and repressors and he has used genetics to demonstrate that those interactions are physiologically relevant for the Transcription process.

The DNA Damage Response

Dr. Norbert Lehming has used the Split-Ubiquitin System to identify interacting partners for the tumor suppressor fumarase. Fumarase, which is a metabolic enzyme of the Krebs Cycle inside the mitochondria, is required for the repair of damaged DNA inside the nucleus. In humans, fumarase was identified as a tumor suppressor because bi-allelic loss-of-function mutations have been linked to Hereditary Leiomyomatosis and Renal Cell Cancer, HLRCC. Fumarase, which interconverts fumarate and malate, was found to interact with nuclear fumarate reductase, which converts fumarate to succinate. Succinate reacts with lysine sidechains of protein in a post-translational modification known as succinylation. With the help of the Split-Ubiquitin System and Mass Spectrometry, Dr. Norbert Lehming is identifying targets of the proposed fumarase-fumarate reductase trans-succinylation complex that are relevant for the repair of damaged DNA.

Project: The molecular mechanisms underlying inflammatory disease

Selected Publications

Leshets M, Ramamurthy D, Lisby M, Lehming N, Pines O (2017) Fumarase is involved in DNA double-strand break resection through a functional interaction with Sae2. Curr Genet [Epub ahead of print] PMID: 29204698 (5 Year Impact Factor 3.341)

Dik E, Naamati A, Asraf H, Lehming N, Pines O (2016) Human Fumarate Hydratase Is Dual Localized by an Alternative Transcription Initiation Mechanism. Traffic 17:720-732. PMID: 27037871 (5 Year Impact Factor 3.963; Citations 1)

Lim MX, Png CW, Tay CY, Teo JD, Jiao H, Lehming N, Tan KS, Zhang Y (2014) Differential regulation of proinflammatory cytokine expression by mitogen-activated protein kinases in macrophages in response to intestinal parasite infection. Infect Immun 82:4789-4801. PMID: 25156742 (5 Year Impact Factor 3.781; Citations 9)

Ee G, Lehming N (2012) How the ubiquitin proteasome system regulates the regulators of transcription. Transcription 3:235-239. PMID: 22885980 (Citations 2)

Ang K, Ee G, Ang E, Koh E, Siew WL, Chan YM, Nur S, Tan YS, Lehming N (2012) Mediator acts upstream of the transcriptional activator Gal4. PloS Biology 10:e1001290. PMID: 22479149 (5 Year Impact Factor 10.206; Citations 7)

Chua CS, Low H, Lehming N, Sim TS (2012) Molecular analysis of Plasmodium falciparum co-chaperone Aha1 supports its interaction with and regulation of Hsp90 in the malaria parasite. Int J Biochem Cell Biol 44:233-245. PMID: 22100910 (5 Year Impact Factor 4.092; Citations 4)

Zhao J, Siew WL, Sun W, Lehming N (2011) The histone variant H2A.Z interconverts two stable epigenetic chromatin states. Biochemical J 439:487-495. PMID: 21736558 (5 Year Impact Factor 4.045)

Lim MK, Siew WL, Zhao J, Tay YW, Ang E, Lehming N (2011) Galactose induction of the GAL1 gene requires conditional degradation of the Mig2 repressor. Biochemical J 435:641-649. PMID: 21323640 (5 Year Impact Factor 4.045; Citations 4)

Chew BS, Siew WL, Xiao B, Lehming N (2010) Transcriptional Activation Requires Protection of the TATA-binding Protein Tbp1 by the Ubiquitin-specific Protease Ubp3. Biochemical J 431:391-399. PMID: 20738257 (5 Year Impact Factor 4.045; Citations 11)

Koh KW, Lehming N, Seah GT (2009) Degradation-resistant protein domains limit host cell processing and immune detection of mycobacteria. Mol Immunol 46, 1312-1318. PMID: 19128836 (5 Year Impact Factor 3.076; Citations 18)

Xue X, Lehming N (2008) Nhp6p and Med3p regulate gene expression by controlling the local subunit composition of RNA polymerase II. J Mol Biol 379, 212-230. PMID: 18448120 (5 Year Impact Factor 3.910; Citations 6)

Lim MK, Tang V, Le Saux A, Schüller J, Bongards C, Lehming N (2007) Gal11p dosage-compensates transcriptional activator deletions via Taf14p. J Mol Biol 374, 9-23. PMID: 17919657 (5 Year Impact Factor 3.910; Citations 12)

Chew BS, Lehming N (2007) TFIIB/SUA7(E202G) is an allele-specific suppressor of TBP1(E186D). Biochemical J 406, 265-271. PMID: 17680779 (5 Year Impact Factor 4.045; Citations 5)

Bongards C, Chew BS, Lehming N (2003) The TATA-binding protein is not an essential target of the transcriptional activators Gal4p and Gcn4p in Saccharomyces cerevisiae. Biochemical J 370, 141-147. PMID: 12423206 (5 Year Impact Factor 4.045; Citations 5)

Schüller J, Lehming N (2003) The cyclin in the RNA polymerase holoenzyme is a target for the transcriptional repressor Tup1p in S. cerevisiae. J Mol Microbiol Biotechnol 5, 199-205. PMID: 12867743 (5 Year Impact Factor 1.756; Citations 7)

He H, Lehming N (2003) Global effects of histone modifications. Briefings in Functional Genomics and Proteomics 2, 234-243. PMID: 15239926 (Citations 55)

Ansari AZ, Koh SS, Zaman Z, Bongards C, Lehming N, Young RA, Ptashne M (2002) Transcriptional activating regions target a cyclin-dependent kinase. Proc Natl Acad Sci USA 99, 14706-14709. PMID: 12417740 (5 Year Impact Factor 10.414; Citations 45)

Lehming N (2002) Analysis of protein-protein proximities using the split-ubiquitin system. Briefings in Functional Genomics and Proteomics 1, 230-238. 15239890 (Citations 14)

Kerkmann K, Lehming N (2001) Genome-wide expression analysis of a S. cerevisiae strain deleted for the Tup1p-interacting protein Cdc73p. Curr Genet 39, 284-290. PMID: 11525400 (5 Year Impact Factor 3.341; Citations 8)

Pätzold AJ, Lehming N (2001) Why Ppr1p is a weak activator of transcription. FEBS Lett 494, 64-68. PMID: 11297736 (5 Year Impact Factor 3.424; Citations 5)

Gromöller A, Lehming N (2000) Srb7p is a physical and physiological target of Tup1p. EMBO J 19, 6845-6852. PMID: 11118219 (5 Year Impact Factor 9.853; Citations 75)

Laser H, Bongards C, Schüller J, Heck S, Johnsson N, Lehming N (2000) A new screen for protein interactions reveals that the Saccharomyces cerevisiae high mobility group proteins Nhp6A/B are involved in the regulation of the GAL1 promoter. Proc Natl Acad Sci USA 97, 13732-13737. PMID: 11095729 (5 Year Impact Factor 10.414; Citations 76)

Gromöller A, Lehming N (2000) Srb7p is essential for the activation of a subset of genes. FEBS Lett 484, 48-54. PMID: 11056220 (5 Year Impact Factor 3.424; Citations 11)

Rojo-Niersbach E, Morley D, Heck S, Lehming N (2000) A new method for the selection of protein interactions in mammalian cells. Biochem J 348, 585-590. PMID: 10839990 (5 Year Impact Factor 4.045; Citations 16)

Wellhausen A, Lehming N (1999) Analysis of the in vivo interaction between a basic repressor and an acidic activator. FEBS Lett 453, 299-304. PMID: 10405164 (5 Year Impact Factor 3.424; Citations 12)

Lehming N, Le Saux A, Schüller J, Ptashne M (1998) Chromatin components as part of a putative transcriptional repressing complex. Proc Natl Acad Sci USA 95, 7322-7326. PMID: 9636147 (5 Year Impact Factor 10.414; Citations 143)

Lehming N, McGuire S, Brickman J, Ptashne M (1995) Interactions of a Rel protein with its inhibitor. Proc Natl Acad Sci USA 92, 10242-10246. PMID: 7479760 (5 Year Impact Factor 10.414; Citations 41)

Lehming N, Thanos D, Brickman JM, Ma J, Maniatis T, Ptashne M (1994) An HMG-like protein that can switch a transcriptional activator to a repressor. Nature 371, 175-179. PMID: 8072548 (5 Year Impact Factor 43.769; Citations 195)

Saha S, Brickman J, Lehming N, Ptashne M (1993) New eukaryotic transcriptional repressors. Nature 363, 648-652. PMID: 8510759 (5 Year Impact Factor 43.769; Citations 85)

Kisters-Woike B, Lehming N, Sartorius J, Wilcken-Bergmann Bv, Müller-Hill B (1991) A model of the lac repressor-operator complex based on physical and genetic data. Eur J Biochem 198, 411-419. PMID: 2040302 (New Name of Journal FEBS  J; 5 Year Impact Factor 4.129; Citations 29)

Sartorius J, Lehming N, Kisters-Woike B, Wilcken-Bergmann Bv, Müller-Hill B (1991) The roles of residues 5 and 9 of the recognition helix of Lac repressor in lac operator binding. J Mol Biol 218, 313-321. PMID: 2010911 (5 Year Impact Factor 3.910; Citations 26)

Lehming N, Sartorius J, Kisters-Woike B, Wilcken-Bergmann Bv, Müller-Hill B (1990) Mutant Lac repressors with new specificities hint at rules for protein-DNA recognition. EMBO J 9, 615-621. PMID: 2178920 (5 Year Impact Factor 9.853; Citations 96)

Sartorius J, Lehming N, Kisters B, Wilcken-Bergmann Bv, Müller-Hill B (1989) Lac repressor mutants with double or triple exchanges in the recognition helix bind specifically to Lac operator variants with multiple exchanges. EMBO J 8, 1265-1270. PMID: 2663473 (5 Year Impact Factor 9.853; Citations 53)

Lehming N, Sartorius J, Oehler S, Wilcken-Bergmann Bv, Müller-Hill B (1988) Recognition helices of Lac and Lambda repressor are oriented in opposite directions and recognize similar sequences. Proc Natl Acad Sci USA 85, 7947-7951. PMID: 3186699 (5 Year Impact Factor 10.414; Citations 93)

Lehming N, Sartorius J, Niemöller M, Geneger G, Wilcken-Bergmann Bv, Müller-Hill B (1987) The interaction of the recognition helix of Lac repressor with Lac operator. EMBO J 6, 3145-3153. PMID: 2826131 (5 Year Impact Factor 9.853; Citations 140)

Laboratory Staff

Jasper Tan
Research Assistant
mictzrj@nus.edu.sg