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Ronit Weisman, Associate Professor

Contact Info

The Open University of Israel Department of Natural and Life Sciences One University Road P.O.B. 808 Ra’anana 4353701, Israel
Office:972-9-778-2188 Fax:972-9-778-0661 Email:ronitwe@openu.ac.il

Additional Information

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Areas Of Interest
  • TOR signaling
  • Growth regulation
  • Cell cycle regulation
  • Genome and epigenome stability

Prof. Ronit Weisman is a senior faculty member in the Department of Natural and Life Sciences at The Open University of Israel (OUI). She obtained her B.Sc. in Life Sciences (summa cum laude) from Tel Aviv University in 1990 and her Ph.D. from the University of Edinburgh in 1995, under the supervision of Prof. Peter Fantes. Her Ph.D studies focused on cell cycle regulation and cyclophilins in the fission yeast S. pombe. She later joined the group of Prof. Yigal Koltin at Tel Aviv University as a postdoctoral fellow (1995-1996) where she initiated her studies on TOR (Target of Rapamycin) signaling in fission yeast. She continued her postdoctoral studies by joining the group of Prof. Mordechai Choder at Tel Aviv University (1997-2000). Subsequently, she joined the group of Prof. Martin Kupiec as a Research Fellow Associate, where she continued to develop her studies on various aspects of TOR signaling (2000-2008). She joined the OUI in 2008 as a Senior Lecturer and received a professorship in 2017. Her research interests concern cellular growth control by TOR signaling and its coordination with the regulation of cell divisions, development, genomic and epigenomic stability. For her research she uses fission yeast, a unicellular organism, which is widely used to tackle basic biological questions. Her studies employ genetic, biochemical, wide-genome and chemical-biology methodologies.

1987 - 1990  B.Sc. Faculty Life Sciences, Tel Aviv University, Tel Aviv, Israel.

1991 - 1995 Direct Ph.D. Institute of Cell and Molecular Biology, Edinburgh University, Edinburgh, UK. Supervisor: Prof. Peter Fantes.

1995 - 1996 Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel. Host: Prof. Yigal Koltin.

1996 - 2000 Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel. Host: Prof. Mordechai Choder.

2000 - 2008 Research fellow Associate, Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel

2006 - 2008 Guest Lecturer, Ruppin Academic Center, Marine Sciences, Israel

2008 - 2010 Guest Senior Lecturer, Department of Natural and Life Sciences, Open University, Israel

2010 - 2017 Senior Lecturer, Department of Natural and Life Sciences, Open University, Israel

2017- Associate Professor, Department of Natural and Life Sciences, Open University, Israel

Cohen, A., Habib, A., Laor, D., Yadav, S., Kupiec, M., and Weisman, R. (2018) TOR complex 2 in fission yeast is required for chromatin-mediated gene silencing and assembly of heterochromatic domains at subtelomeres. Journal of Biological Chemistry 21: 8138-8150

Pataki, E., Weisman, R, Sipiczki, M. and Miklos, I. (2016) fhl1 gene of the fission yeast regulates transcription of meiotic genes and nitrogen starvation response, downstream of the TORC1 pathway. Current Genetics 63:91-101.

Cohen, A., Kupiec, M. and Weisman, R. (2016) TORC2-Gad8 is found in the nucleus where it interacts with the MBF transcriptional complex to regulate the response to DNA replication stress. Journal of Biological Chemistry, 291:9371-81.

Laor, D., Cohen, A., Kupiec, M., Weisman, R. (2015) TORC1 regulates developmental responses to nitrogen stress via nuclear localization of the GATA transcription factor Gaf1. mBio, 7;6(4):e00959. doi: 10.1128/mBio.00959-15.

Cohen, A., Kupiec, M. and Weisman, R. (2014) Glucose activates TORC2-Gad8 via positive regulation of the cAMP/PKA pathway and negative regulation of the Pmk1-MAPK pathway. Journal of Biological Chemistry, 289:21727-37.

Weisman, R. Cohen, A. and Gasser, S. (2014) TORC2 – A new player in genome stability. EMBO Molecular Medicine, 6:995-1002.

Ding, L., Laor, D., Weisman, R. and Forsburg, S. (2014) Rapid regulation of nuclear proteins by rapamycin-induced translocation in fission yeast. Yeast, 31:253-64.

Laor, D., Cohen, A., Pasmanik-Chor, M., Oron-Karni, V., Kupiec, M., Weisman, R.(2013) Isp7 is a novel regulator of amino acid uptake in the TOR signaling pathway. Molecular and Cellular Biology, 34:794-806.

Schonbrun, M., Kolesnikov, M., Kupiec, M. and Weisman, R. (2013) TORC2 is required to maintain genome stability during S phase in fission yeast. Journal of Biological Chemistry, 288:19649-60.

Kupiec, M. and Weisman, R. (co-author) (2012) TOR links starvation responses to telomere length maintenance. Cell Cycle, 11:2268-71.

Schonburn, M. Laor, D. Maury, L., Bahler, J., Kupiec, M. and Weisman R. (2009) TOR complex 2 controls gene silencing, telomere length maintenance, and survival under DNA-damaging conditions. Molecular and Cellular Biology, 29: 4584-4594.

Weisman, R., Roitburg, I., Schonburn, M., Harari, R. and Kupiec, M. (2007) Opposite effects of Tor1 and Tor2 on nitrogen starvation responses in fission yeast. Genetics, 175:1153-1162.

Weisman, R., Roitburg, I., Nahari, T. and Kupiec, M. (2005) Regulation of leucine uptake by tor1+ in fission yeast is sensitive to rapamycin. Genetics, 169:539-550.

Weisman, R.  (2003) The fission yeast TOR proteins and rapamycin response: an unexpected tale. (Invited review). Current Topics in Microbiology and Immunology, 279:85-95.

Weisman, R., Finkelstein, S. and Choder, M. (2001) Rapamycin blocks sexual development in fission yeast through inhibition of the cellular function of an FKBP12 homologue. Journal of Biological Chemistry, 276: 24736-24742.

Weisman, R. and Choder, M. (2001) The fission yeast TOR homologue, tor1+, is required for the response to starvation and other stresses via a conserved serine. Journal of Biological Chemistry, 276: 7027-7032.

Samejima, I., Mackie, S., Warbrick, E., Weisman, R. and Fantes, P. (1998) The fission yeast mitotic regulator win1+ encodes an MAP kinase kinase kinase that phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity. Molecular and Cellular Biology, 9, 2325-2335.

Weisman, R., Choder, M., and Koltin, Y. (1997) Rapamycin specifically interferes with the developmental response of fission yeast to starvation. Journal Bacteriology, 179, 6325-6334.

Weisman, R., Creanor J. and Fantes, P.A. (1996) A multicopy suppressor of a cell cycle defect in S.pombe encodes a heat shock inducible 40 kDa cyclophilin-like protein. EMBO Journal, 15, 447-456.

Fonseca, B.D., Graber, T.E., Hoang, H-D., González, A., Soukas, A.A., Hernández, G., Alain, T., Swift, S.L., Weisman, R., Meyer, C., Robaglia, C.,Avruch, J., Hall, M.N. Evolution of the TOR Pathway Across Eukaryotes. In: Hernández, G. and Jagus, R (eds.). Evolution of the Protein Synthesis Machinery and Its Regulation.  Springer International Publishing, 2016, pp. 327-411

Weisman, R. TOR senses amino acids and controls cell growth. In: The Fungal Kingdom. Joseph Heitman, Barbara Howlett, Pedro Crous, Eva Stukenbrock, Timothy James, and Neil Gow (eds.) ASM Press. 2016 
*This book chapter is also published as an independent review in the ASM journal Microbiology Spectrum. 2016 Oct;4(5). doi:10.1128/microbiolspec. FUNK-0006-2016.

Weisman, R. Fission Yeast TOR and Rapamycin. In: M. Hall and F. Tamanoi, (eds.) The Enzymes: TOR complexes from yeast to mammals, Vol. 27, Burlington: Academic Press, 2010, pp.251-269.

Cellular growth control by TOR signaling 
 
Cellular growth, proliferation and differentiation are key aspects of cellular biology. The TOR signaling pathway is most well-known for its role in promoting cellular growth programs, while inhibiting starvation responses. Other distinguishing features of the TOR pathway are its unique role in regulating cell, organs and whole body size, as well as its role in regulating aging. More recently, TOR has been shown to regulate certain aspects of genomic and epigenomic stability, further extending the scope of the cellular functions of the TOR proteins. Deregulation of TOR signaling is observed in many different pathological conditions, including cancer, as well as neurodegenerative and metabolic diseases. TOR specific inhibitors have already been approved for medical use.

TOR is a large (~280 kDa), a-typical protein kinase that belongs to the family of phosphatidylinositol 3-kinase-related kinases and is conserved in eukaryotes. The first TOR genes were isolated in the budding yeast Saccharomyces cerevisiae in a genetic screen for rapamycin resistant mutant cells, hence the name TOR, for Target of Rapamycin. Critical aspects of TOR signaling and the mode of action of rapamycin were also first discovered in S. cerevisiae, demonstrating the importance of using yeast for biomedical research.

Rapamycin, which specifically inhibits the activity of TOR, is a small molecule that is produced by a soil bacterium. It has several important clinical implications, including in immunosuppressive and cancer therapy. An intriguing property of rapamycin is the expansion of life span in model organisms, an effect that is likely associated with that of calorie restriction. Since rapamycin only inhibits a sub-set of TOR-dependent functions, next-generation TOR inhibitors have been developed. The search for additional TOR inhibitors that will modulate TOR signaling is one of the important challenges that researchers face in the TOR field. 

TOR kinases serve as the catalytic subunit of two protein complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The cellular function of TORC1 is better understood, partly since rapamycin is a potent inhibitor of TORC1 but not of TORC2. TORC1 is a pro-growth complex that promotes anabolic processes such as, translation, ribosome biogenesis, nucleotides and lipid synthesis, while inhibiting catabolic processes such as autophagy. The cellular role of TORC2 is far less well-understood. TORC2 regulates growth and cell survival via the phosphorylation and activation of distinct protein kinases, such as AKT, SGK1 and PKC in human cells, YPK1/2 in S. cerevisiae or Gad8 in S. pombe. Deregulation of TORC2 is closely associated with cancer development, thus, further understanding of TORC2 signaling is much sought-after.

We employ the rod-shaped yeast Schizosaccharomyces pombe to study TOR signaling. The benefits of studying TOR in S. pombe include all the benefits of studying a complex signaling pathway in a genetic tractable organism, as well as the advantages unique to S. pombe, such as a notable evolutionarily conservation to human cells with respect to certain aspects of TOR signaling.

The two TOR complexes are conserved in S. pombe (see Fig. 1). The catalytic subunit of SpTORC1 is designated Tor2 and the catalytic subunit of SpTORC2 is designated Tor1. This somewhat confusing designation is the result of naming the S. pombe Tor1 and Tor2 genes according the chronological order by which they were identified, several years before the isolation and naming of the TOR complexes in S. cerevisiae. Several labs, including ours, have shown that while SpTORC1 is activated in response to the nitrogen quantity and quality, or the presence of specific amino acids, SpTORC2 is responsive to glucose levels.


 

 

 

Figure 1: TORC1 and TORC2 in S. pombe – representative cellular activities

Upon reduction in the quantity or quality of the nitrogen source, SpTORC1 is inactivated, leading to growth arrest and induction of starvation responses, such as sexual development and autophagy. SpTORC1 plays a major role in regulating transcription in response to nitrogen availability. We demonstrated that SpTORC1 regulates the nuclear localization of the GATA transcription factor Gaf1 in a manner dependent on type2A-related serine/threonine phosphatase (PP2A). By regulating Gaf1 phosphorylation and cellular localization, SpTORC1 affects sexual development and amino acid uptake in response to nitrogen availability (Fig. 2).

 

 

Figure 2: SpTORC1 regulates the nitrogen starvation response via localization of Gaf1 into the nucleus

SpTORC2 is not essential under normal growth conditions, but is required for timely regulation of cell cycle progression, starvation responses, and survival under a wide variety of cellular stresses, including temperature, osmotic and nutritional stresses. Intriguingly, SpTORC2 is also required for survival under DNA damage and DNA replication stress conditions. Our transcriptional profile analyses of cells lacking the catalytic subunit of SpTORC2 or its downstream effector, the Gad8 kinase, unexpectedly indicated an extensive similarity with chromatin structure mutants. This finding has led us to unravel the role of SpTORC2 in DNA damage response, telomere length maintenance and gene silencing. SpTORC2-Gad8 affects genome stability via suppressing accumulation of DNA damage sites (Fig.3) and by preventing chromosomal loss. The mechanisms underlying the genome instability in SpTORC2 mutant cells are still unclear and are currently under investigation. A first clue as to the possible mechanisms by which SpTORC2 affects tolerance to DNA-damaging conditions is our finding showing that the catalytic subunit of SpTORC2, as well as the Gad8 kinase interact with, and are required for the loading onto chromatin of the Mlu-binding factor (MBF) transcription complex. In turn, the MBF complex induces transcription of genes required for the G1/S phase transition and DNA damage repair. We have also found that SpTORC2-Gad8 affects epigenomic stability. SpTORC2-Gad8 is required for gene silencing and H3 lysine-9 (H3K9) methylation of facultative heterochromatin in a manner antagonistic to the action of the RNA polymerase II -associated Paf1C complex. These findings suggest that SpTORC2 may link nutritional control to epigenetic traits.

Figure 3: Elevated levels of DNA damage (Rad52-YFP) foci in SpTORC2 mutant cell.

Rad52-YFP foci are observed as small dots within the blue-stained nuclei.

 

 Research Goals

Our long-term goal is to understand how growth is regulated in eukaryotes and coordinated with cell divisions, development, genomic and epigenomic stability.

Current goals in the lab:

• Isolation of proximal and distal effectors of TORC1 and TORC2
 
• Understanding the mode of activation of TORC1 and TORC2

• Use of genetically engineered yeast cells to screen for novel anti-TOR inhibitors

 

  • Post-graduate students
    2016-present  Emese Pataki
    2014-2015  Dana Laor
    2012-2014   Sudhanshu Yadav

    Ph.D. students
    Co-supervision, together with Prof. Martin Kupiec, Tel Aviv University
    2009-2014 Dana Laor
    Title thesis: "The cellular roles of TOR in nitrogen stress response in Schizosaccharomyces pombe"
    2007-2012  Miriam Schonbrun
    Title thesis: "Involvement of the fission yeast TOR signaling pathway in the replication and DNA damage response”

    M.Sc. students
    Co-supervision, together with Prof. Martin Kupiec, Tel Aviv University
    2017-   Nuriya Vital
       Title thesis: To be determined
    2015-2017  Aline Habib
       Title thesis:"TORC2 affects gene silencing and chromatin states"
    2014-2017  Sophie Reidman
    Title thesis: "Nitrogen metabolism and TOR signaling in fission yeast"
    2009-2011  Masha Kolesnikov
    Title thesis: "The TOR pathway is involved in gene silencing and DNA damage response in Schizosaccharomyces pombe"
    2007-2009  Dana Laor.
    Title thesis: "The TOR pathway regulates cellular growth, gene silencing and telomere length maintenance in Schizosaccharomyces pombe"
    2005-2007  Miriam Schonbrun
    Title of thesis: “The TOR pathway regulates cellular growth and division in response to environmental changes in Schizosaccharomyces pombe
  • • Cell Structure and Function
    • The World of Bacteria
    • Human Genetics
    • Nutrition
    • Laboratory – Cell Biology
    • Stem Cells – advanced seminar
    • Selected Topics in Cell Biology – advanced seminar
  • 2017 Laboratory in Biotechnology (new course)
    2015  Cell structure and Function (new course)
    Genetics – updating existing materials
    Stem cells – updating existing materials
    2014   Human Genetics – updating existing materials
     Selected topics in Cell Biology (new course)
    2013 Cell Structure and function – updating existing materials
    2011 Laboratory in Cell Biology – (new course)
  • 2011 B.Sc. in Life Sciences: Emphasis on Molecular and Cellular Biology

Research group

Current members
Adi Cohen  (Senior Research Assistant, The Open University of Israel)
Emese Pataki (Post-Doc, The Open University of Israel)
Nuria Vital  (M.Sc., Tel Aviv University, Jointly supervised with Prof. Martin Kupiec)

Past members
Sophie Reidman (M.Sc., Tel Aviv University, Jointly supervised with Prof. Martin Kupiec)
Aline Habib  (M.Sc., Tel Aviv University, Jointly supervised with Prof. Martin Kupiec)
Sudhansu Yadav (Post-Doc, The Open University of Israel)
Masha Kolesnikov (M.Sc., Tel Aviv University, Jointly supervised with Prof. Martin Kupiec)
Dana Laor  (M.Sc. & Ph.D., Tel Aviv University, Jointly supervised with Prof. Martin Kupiec)
Miriam Schonbrun (M.Sc. & Ph.D., Tel Aviv University, Jointly supervised with Prof. Martin Kupiec)