Picture of Eric Fischer
Eric Sebastian Fischer, Ph.D.
Assistant Professor of Biological Chemistry and Molecular Pharmacology

We combine structural biology, cell biology and biochemical reconstitutions to address the molecular workings of multi-protein ubiquitin ligase complexes. In particular, we are interested in protein complexes and pathways that contribute to the control of gene expression and are frequently associated with human disease and cancer.

 

Research:

The Ubiquitin Proteasome System (UPS) is involved in virtually any cellular process and frequently implicated in human pathologies. Ubiquitin, through the action of a three-enzyme cascade (E1, E2 and E3), is covalently attached to substrate proteins. The posttranslational modification with ubiquitin can serve a multitude of functions depending on the type and length of the ubiquitin chain attached to the substrate, including the control of protein abundance via proteasomal degradation. The human genome encodes for more than 600 E3 ligases, which confer specificity in the ubiquitin signaling cascade. While the process of ubiquitin transfer is well understood, the biological function and molecular mechanisms of the majority of ubiquitin ligases remain obscure.

We combine structural biology, cell biology and biochemical reconstitutions to address the molecular workings of multi-protein ubiquitin ligase complexes. In particular, we are interested in protein complexes and pathways that contribute to the control of gene expression and are frequently associated with human disease and cancer. Intimate understanding of the structure allows us to dissect the complex mechanisms that underlie function and regulation of such molecules and to probe their biology in a cellular context.

We seek to leverage our molecular understanding to propose and test new avenues of therapeutic intervention. We are also interested in small molecules targeting the UPS such as the anti-cancer therapeutics thalidomide and derivatives. As before, we utilize a broad toolset of structural biology, proteomics, cell biology and biochemical reconstitutions to elucidate their activities and precise mode of action.

Address: 

Dana-Farber Cancer Institute

Longwood Center 4312

360 Brookline Ave

Boston, MA 02215

Publications View
Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations.
Authors: Authors: de Wispelaere M, Du G, Donovan KA, Zhang T, Eleuteri NA, Yuan JC, Kalabathula J, Nowak RP, Fischer ES, Gray NS, Yang PL.
Nat Commun
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Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6.
Authors: Authors: Jiang B, Wang ES, Donovan KA, Liang Y, Fischer ES, Zhang T, Gray NS.
Angew Chem Int Ed Engl
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Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models.
Authors: Authors: Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, Zhang T, Huang HT, Lucente DE, Dickerson BC, Mitchison TJ, Fischer ES, Gray NS, Haggarty SJ.
Elife
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Bruton tyrosine kinase degradation as a therapeutic strategy for cancer.
Authors: Authors: Dobrovolsky D, Wang ES, Morrow S, Leahy C, Faust T, Nowak RP, Donovan KA, Yang G, Li Z, Fischer ES, Treon SP, Weinstock DM, Gray NS.
Blood
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Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML.
Authors: Authors: Brand M, Jiang B, Bauer S, Donovan KA, Liang Y, Wang ES, Nowak RP, Yuan JC, Zhang T, Kwiatkowski N, Müller AC, Fischer ES, Gray NS, Winter GE.
Cell Chem Biol
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Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity.
Authors: Authors: Sievers QL, Gasser JA, Cowley GS, Fischer ES, Ebert BL.
Blood
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Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome.
Authors: Authors: Donovan KA, An J, Nowak RP, Yuan JC, Fink EC, Berry BC, Ebert BL, Fischer ES.
Elife
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Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance.
Authors: Authors: Zhou W, Whiteley AT, de Oliveira Mann CC, Morehouse BR, Nowak RP, Fischer ES, Gray NS, Mekalanos JJ, Kranzusch PJ.
Cell
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Plasticity in binding confers selectivity in ligand-induced protein degradation.
Authors: Authors: Nowak RP, DeAngelo SL, Buckley D, He Z, Donovan KA, An J, Safaee N, Jedrychowski MP, Ponthier CM, Ishoey M, Zhang T, Mancias JD, Gray NS, Bradner JE, Fischer ES.
Nat Chem Biol
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Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).
Authors: Authors: Powell CE, Gao Y, Tan L, Donovan KA, Nowak RP, Loehr A, Bahcall M, Fischer ES, Jänne PA, George RE, Gray NS.
J Med Chem
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