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    Jennifer A Benanti PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-525
    Worcester MA 01605
    Phone508-856-1773
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Gene Function and Expression

        Overview 
        Narrative

        Academic Background

        Jennifer Benanti received her B.S. from the University of California, San Diego in 1996, and her Ph.D. from the University of Washington and the Fred Hutchinson Cancer Research Center in 2003. She did her postdoctoral work at the University of California, San Francisco from 2004-2010, where she was supported by a Damon Runyon Cancer Research Foundation Fellowship and a Pathway to Independence Award from the NIH. She joined the Program in Gene Function and Expression at the University of Massachusetts Medical School in spring 2010.

        Regulation of Cell Growth and Division

        Jennifer BenantiMisregulation of cell division is the underlying cause of a number of human diseases, including cancer. Our lab is interested in understanding the molecular mechanisms that control how cells grow and divide. We study how protein degradation by the ubiquitin proteasome system controls both the cell cycle and metabolic transitions.

        Identification of ubiquitin ligase targets

        Proteins are marked for degradation by the covalent attachment of ubiquitin chains, which target proteins to the proteasome for destruction (see Figure 1). Ubiquitin ligases recognize specific protein substrates and catalyze the final step of the ubiquitin conjugation pathway. This is the most highly regulated step of the pathway, consistent with the fact that there are approximately 1000 distinct ubiquitin ligases in human cells. Despite their critical roles in cellular biology, substrates have only been identified for a small fraction of these ligases.

        Figure 1. The ubiquitin proteasome system.

        Figure 1. The ubiquitin proteasome system. Proteins are marked for degradation in the proteasome by the addition of chains of ubiquitin molecules to a lysine side chain of a target protein. The conjugation of ubiquitin to a substrate requires the action of three enzymes. First, the energy of ATP is used to generate a thioester bond between ubiquitin (Ub) and a ubiquitin activating enzyme (E1). This Ub molecule is then transferred from the E1 to a ubiquitin conjugating enzyme (E2). Finally, a ubiquitin ligase (E3) directs transfer of the ubiquitin to a specific protein substrate. Subsequent ubiquitin molecules are added to a lysine side chain in the first Ub molecule, and when the chain reaches at least 4 ubiquitin molecules in length, the protein is shuttled to the proteasome and degraded.

        We are using budding yeast as a model organism to identify new targets of ubiquitin ligases. To this end, we have screened the entire yeast proteome using a collection of yeast strains in which each open reading frame is tagged with GFP, in order to identify all targets of individual ubiquitin ligases. Using quantitative, high-throughput microscopy we identified GFP-tagged proteins that increase in abundance when a specific ubiquitin ligase gene is deleted (see Figure 2). This approach has led to the identification of new targets of two ubiquitin ligases that have central roles in controlling cell cycle progression, the Skp1-Cullin-F-box (SCF) complex and the Anaphase-Promoting Complex (APC). We are currently examining the biological significance of several of these new targets.

        Figure 2. Identification of APC(Cdh1) targets.

        Figure 2. Identification of APCCdh1 targets. To identify proteins that increase in levels when the APC activator Cdh1 is deleted, wild type (RFP negative) and cdh1Δ::RFP (RFP positive) cells, each expressing the same GFP-tagged protein, were mixed together and imaged in 96-well plates. Average GFP intensity per cell was calcuated, and levels were compared between wild type and cdh1Δ populations. Shown here are the APCCdh1 targets Spo12 and Cik1, both of which are brighter green in cells that are RFP positive (cdh1Δ).

        Cell cycle control by ubiquitin ligases

        Although the SCF and APC have well established roles in regulating the cell cycle, deletion of several other ubiquitin ligase genes cause cell cycle defects. To gain a better understanding of how other ligases may contribute to cell cycle regulation, we recently identified 75 cell cycle proteins that are degraded rapidly, and have screened all ubiquitin ligases in budding yeast (~50) to identify which ubiquitin ligase targets each of these proteins for degradation. Ongoing projects focus on elucidating the mechanism by which these proteins are targeted to ubiquitin ligases, constructing non-degradable versions of these proteins, to assess the importance of their turnover for cell cycle progression, and identifying the functions of uncharacterized ubiquitin ligases.

        Regulation of metabolic switches

        Cell growth is tightly coupled to the cell cycle so that cells only divide when the necessary resources are available. We are interested in the role that ubiquitin-mediated degradation plays in how cells adapt to nutrient availability and growth conditions. One ubiquitin ligase that controls nutrient sensing in yeast is SCFGrr1. Previously, we found that SCFGrr1 has several targets that function to activate or deactivate the glycoloysis pathway, depending on the availability of extracellular glucose. Surprisingly, each of these targets is ubiquitinated by SCFGrr1 following phosphorylation by a different kinase. We are working to identify the signalling pathways that lead to destruction of these glycolytic regulators.

        Hyperactivation of glycolysis is also a feature of many cancer cells, and mammailan homologues of glycolytic SCFGrr1 targets are upregulated in a number of cancer types. We are also investigating whether glycolytic regulators are regulated by the ubiquitin proteasome pathway in mammalian cells, and attempting to identify ubiquitin ligases that regulate this pathway.



        Rotation Projects

        Rotation Projects

        Several rotation projects are available in the lab, depending on a student’s particular interest. Most projects will involve a combination of cell biology, biochemistry, and yeast genetics to study the functions of ubiquitin ligases. Our recent screen of cell cycle proteins has opened up a number of potential projects that focus on how individual proteins are targeted for degradation by specific ubiquitin ligases, and understanding how regulated turnover of each protein contributes to the fidelity of the cell cycle. Other project possibilities include identifying functions and targets of uncharacterized ubiquitin ligases, and studying the role of protein turnover in how cells adapt to changes in the availability of nutrients.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Please contact Dr. Benanti for details.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Landry BD, Mapa CE, Arsenault HE, Poti KE, Benanti JA. Regulation of a transcription factor network by Cdk1 coordinates late cell cycle gene expression. EMBO J. 2014 Apr 8.
          View in: PubMed
        2. Edenberg ER, Vashisht A, Benanti JA, Wohlschlegel J, Toczyski DP. Rad53 downregulates mitotic gene transcription by inhibiting the transcriptional activator ndd1. Mol Cell Biol. 2014 Feb; 34(4):725-38.
          View in: PubMed
        3. Landry BD, Doyle JP, Toczyski DP, Benanti JA. F-box protein specificity for g1 cyclins is dictated by subcellular localization. PLoS Genet. 2012 Jul; 8(7):e1002851.
          View in: PubMed
        4. Benanti JA. Coordination of cell growth and division by the ubiquitin-proteasome system. Semin Cell Dev Biol. 2012 Apr 19.
          View in: PubMed
        5. Benanti JA, Matyskiela ME, Morgan DO, Toczyski DP. Functionally distinct isoforms of Cik1 are differentially regulated by APC/C-mediated proteolysis. Mol Cell. 2009 Mar 13; 33(5):581-90.
          View in: PubMed
        6. Benanti JA, Toczyski DP. Cdc20, an activator at last. Mol Cell. 2008 Nov 21; 32(4):460-1.
          View in: PubMed
        7. Benanti JA, Wang ML, Myers HE, Robinson KL, Grandori C, Galloway DA. Epigenetic down-regulation of ARF expression is a selection step in immortalization of human fibroblasts by c-Myc. Mol Cancer Res. 2007 Nov; 5(11):1181-9.
          View in: PubMed
        8. Benanti JA, Cheung SK, Brady MC, Toczyski DP. A proteomic screen reveals SCFGrr1 targets that regulate the glycolytic-gluconeogenic switch. Nat Cell Biol. 2007 Oct; 9(10):1184-91.
          View in: PubMed
        9. Vega LR, Phillips JA, Thornton BR, Benanti JA, Onigbanjo MT, Toczyski DP, Zakian VA. Sensitivity of yeast strains with long G-tails to levels of telomere-bound telomerase. PLoS Genet. 2007 Jun; 3(6):e105.
          View in: PubMed
        10. Benanti JA, Galloway DA. The normal response to RAS: senescence or transformation? Cell Cycle. 2004 Jun; 3(6):715-7.
          View in: PubMed
        11. Benanti JA, Galloway DA. Normal human fibroblasts are resistant to RAS-induced senescence. Mol Cell Biol. 2004 Apr; 24(7):2842-52.
          View in: PubMed
        12. Benanti JA, Williams DK, Robinson KL, Ozer HL, Galloway DA. Induction of extracellular matrix-remodeling genes by the senescence-associated protein APA-1. Mol Cell Biol. 2002 Nov; 22(21):7385-97.
          View in: PubMed
        13. Passalaris TM, Benanti JA, Gewin L, Kiyono T, Galloway DA. The G(2) checkpoint is maintained by redundant pathways. Mol Cell Biol. 1999 Sep; 19(9):5872-81.
          View in: PubMed
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