Michael French
Office
McCardell Bicentennial Hall
Tel
(802) 443-3094
Email
mfrench@middlebury.edu
Office Hours
Spring 2022: Tues. and Thurs. from 12:30-2 p.m. and by appointment
Additional Programs
Chemistry and Biochemistry

My research group focuses on the molecular mechanisms of protein degradation, with an emphasis on understanding the biochemistry of how ubiquitin ligases work. In eukaryotic organisms, proteins that are damaged, misfolded, or no longer needed are degraded through a specialized pathway known as the ubiquitin-proteasome system. In this system, the small protein modifier ubiquitin is covalently attached to a protein substrate, usually in the form of a polyubiquitin chain, by a series of enzymes. The ubiquitinated protein, marked for destruction, is then shuttled to a large, multi-subunit complex known as the proteasome, which unfolds the protein substrate and cleaves it into pieces. Current work in my group is focused on understanding how ubiquitin ligases, the key regulatory enzymes in this cascade, modify their substrates with different types of polyubiquitin chains. We are specifically interested in understanding how the Nedd4 family of ubiquitin ligases, which consists of nine different members in humans, builds polyubiquitin chains on its substrates. Recent work suggests a two-phase mechanism that imparts these enzymes with the ability to synthesize two distinct types of polyubiquitin signals, the functions of which have yet to be fully defined (French et al., JBC 2017; Ohtake et al., PNAS, 2018). Using the tools of biochemistry and proteomics, we seek to understand the general relevance and functional importance of this mechanism for ubiquitin ligases within the Nedd4 family.

Courses Taught

Course Description

General Chemistry I
Major topics will include atomic theory and atomic structure; chemical bonding; stoichiometry; introduction to chemical thermodynamics. States of matter; solutions and nuclear chemistry. Laboratory work deals with testing of theories by various quantitative methods. Students with strong secondary school preparation are encouraged to consult the department chair for permission to elect CHEM 0104 or CHEM 0107 in place of this course. CHEM 0103 is also an appropriate course for a student with little or no prior preparation in chemistry who would like to learn about basic chemical principles while fulfilling the SCI or DED distribution requirement. 3 hrs. lect., 3 hrs. lab, 1 hr. disc.

Terms Taught

Fall 2020, Spring 2021, Fall 2021

Requirements

DED, SCI

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Course Description

Instrumental Analysis
In this course we will learn fundamental concepts of analytical chemistry, instrumental analysis, and scientific writing. Lecture topics include experimental design and quality control; sample collection and preparation; calibration, error, and data analysis; statistics; and the theory and operation of chemical instrumentation. Multi-week laboratory projects provide hands-on experience in qualitative and quantitative analysis using a variety of research-quality instrumentation (e.g., UV/Vis spectrophotometry, gas chromatography mass spectrometry, inductively coupled plasma mass spectrometry). Writing workshops promote professional scientific writing skills through guided practice in writing analysis, peer review, and revision. (CHEM 0204 or CHEM 0242) 3 hr. lect., 6 hrs. lab.

Terms Taught

Fall 2020

Requirements

CW

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Course Description

Biochemistry Laboratory
Experimental biochemistry emphasizing the isolation, purification and characterization of enzymes and the cloning of genes and expression of recombinant protein. Traditional biochemical techniques such as UV-VIS spectroscopy, gel filtration, ion exchange and affinity chromatography, electrophoresis, and immunoblotting will be used in the investigation of several enzymes. Specific experiments will emphasize enzyme purification, enzyme kinetics, and enzyme characterization by biochemical and immunochemical methods. Major techniques in molecular biology will be introduced through an extended experiment that will include DNA purification, polymerase chain reaction, bacterial transformation, DNA sequencing, and the expression, purification, and characterization of the recombinant protein. Class discussions emphasize the underlying principles of the biochemical and molecular techniques employed in the course, and how these experimental tools are improved for particular applications. Laboratory reports stress experimental design, data presentation, and interpretation of results. (CHEM 0322) 2 hr. lect., 6 hrs. lab.

Terms Taught

Spring 2022

Requirements

CW

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Course Description

Biochemistry of Macromolecules
This course is an introduction to biochemistry that focuses on the chemical and physical properties of amino acids, proteins, lipids, carbohydrates, and nucleic acids. Specific topics include the structure and function of proteins, enzyme mechanisms and kinetics, how carbohydrates and lipids contribute to vital cellular and organismal functions, and informational biochemistry (DNA, RNA, and specific enzymes and processes leading to the production of regulatory RNA and proteins). Specific topics from the primary literature will be explored to illustrate how particular techniques and experimental approaches are used to gain a new understanding of biochemistry and molecular biology. (CHEM 0203 or CHEM 0242) 3 hrs. lect., 1 hr. disc.

Terms Taught

Spring 2021, Spring 2022

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Course Description

Independent Study Project
Individual study for qualified students. (Approval required)

Terms Taught

Winter 2021, Spring 2021, Fall 2021, Winter 2022, Spring 2022, Winter 2023

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Course Description

Senior Research
In this course students complete individual projects involving laboratory research on a topic chosen by the student and a faculty advisor. Prior to registering for CHEM 0700, a student must have discussed and agreed upon a project topic with a faculty member in the Chemistry and Biochemistry Department. Attendance at all Chemistry and Biochemistry Department seminars is expected. (Approval required; open only to seniors)

Terms Taught

Winter 2021, Spring 2021, Fall 2021, Winter 2022, Spring 2022, Winter 2023

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Course Description

Senior Thesis
Students who have initiated research projects in CHEM 0400 and who plan to complete a senior thesis should register for CHEM 0701. Students are required to write a thesis, give a public presentation, and defend their thesis before a committee of at least three faculty members. The final grade will be determined by the department. Attendance at all Chemistry and Biochemistry Department seminars is expected. (CHEM 0400; approval required)

Terms Taught

Winter 2021, Spring 2021, Fall 2021, Winter 2022, Spring 2022, Winter 2023

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Course Description

Senior Independent Research
Seniors conducting independent research in Molecular Biology and Biochemistry under the guidance of a faculty mentor should register for MBBC 0700 unless they are completing a thesis project (in which case they should register for MBBC 0701). Additional requirements include attendance at all MBBC-sponsored seminars and seminars sponsored by the faculty mentor’s department, and participation in any scheduled meetings and disciplinary sub-groups and lab groups. (Approval required).

Terms Taught

Fall 2020, Winter 2021, Spring 2021, Fall 2021, Winter 2022, Spring 2022, Winter 2023

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Course Description

Senior Thesis
This course is for seniors completing independent thesis research in Molecular Biology and Biochemistry that was initiated in BIOL 0500, CHEM 0400, MBBC 0500, or MBBC 0700. Students will attend weekly meetings with their designated research group and engage in one-on-one meetings with their research mentor to foster understanding in their specialized research area. Students will also practice the stylistic and technical aspects of scientific writing needed to write their thesis. (BIOL 0500, CHEM 0400, MBBC 0500, MBBC 0700) (Approval required).

Terms Taught

Spring 2021, Fall 2021, Spring 2022

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Course Description

Senior Research
This course is for senior NSCI majors who plan to conduct one or more semesters of independent research, or who plan to complete preparatory work toward a senior thesis, such as researching and writing a thesis proposal as well as, if appropriate, collecting data that will form the basis for a senior thesis. Senior NSCI majors who plan to complete a senior thesis should register initially for NSCI 0700. Additional requirements may include participation in weekly meetings with advisors and/or lab groups and attending neuroscience seminars. (Approval required, open to seniors only)

Terms Taught

Fall 2021, Winter 2022, Fall 2022, Winter 2023, Fall 2023

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Course Description

Senior Thesis
Senior NSCI majors who have completed one or more terms of NSCI 0700, who have a GPA of 3.3 in their major courses, and who plan to complete a senior thesis should register for NSCI 0701 for the final semester of the senior thesis process. Students enrolled in NSCI 0701 write a thesis, give a public presentation of their research, and present an oral defense of the thesis before a committee of at least two Neuroscience faculty members. Faculty may recommend High honors in Neuroscience after considering the quality of these components of a student’s thesis and the student’s GPA in major courses. Additional requirements may include participation in weekly meetings with advisors and/or lab groups and attending neuroscience seminars. (NSCI 0700, Approval required)

Terms Taught

Fall 2021, Spring 2022, Fall 2022, Spring 2023, Fall 2023, Spring 2024

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Academic Degrees

B.S./M.S., Biochemistry/Cell Biology, Bucknell University
Ph.D., Biochemistry and Molecular Biology, Northwestern University
Postdoctoral Fellowship, The Scripps Research Institute and The Salk Institute

Publications

French, M.E., Koehler, C.*, and Hunter T. Emerging functions of branched ubiquitin chains. Cell Discov., 7(1):6, 2021*C. Koehler is a former undergraduate student at Grinnell College

French, M.E., Klosowiak, J.L., Aslanian, A., Reed, S.I., Yates, J.R. III and Hunter, T. Mechanism of ubiquitin chain synthesis employed by a HECT domain ubiquitin ligase. J. Biol. Chem. 292:10398-10413, 2017.

Klosowiak, J.L., Park, S.N., Smith, K.P., French, M.E., Focia, P.J., Freymann, D.M. and Rice, S.E. Structural insights into Parkin substrate lysine targeting from minimal Miro substrates. Sci. Rep. 6:33019, 2016.

French, M.E., Kretzmann, B.R.* and Hicke, L. Regulation of the Rsp5 ubiquitin ligase by an intrinsic ubiquitin-binding site. J. Biol. Chem. 284:12071-12079, 2009. *B.R. Kretzmann is a former undergraduate student advisee at Northwestern University

Stamenova, S.D., French, M.E., He, Y., Francis, S., Kramer, Z.* and Hicke, L. Ubiquitin binds to and regulates a subset of SH3 domains. Mol. Cell 25:273-284, 2007. *Z. Kramer is a former undergraduate student advisee at Northwestern University

French, M.E., Swanson, K., Shih, S., Radhakrishnan, I. and Hicke, L. Identification and characterization of modular domains that bind ubiquitin. Methods Enzymol. 399:135-157, 2005.

Zhou, L., Thompson, R., Reamer, R.A., Lin, Z., French, M., Ellison, D. and Wyvratt, J. Mechanistic study of the enantiomeric recognition of a basic compound with negatively charged single isomer gamma-cyclodextrin derivatives using capillary electrophoresis, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. Electrophoresis 24:2448-2455, 2003.

Zhou, L., Thompson, R., French, M., Ellison, D. and Wyvratt, J. Simultaneous enantioseparation of a basic drug compound and its acidic intermediate by capillary electrophoresis. J. Sep. Sci. 25:1183-1189, 2002.