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Mark Hochstrasser, PhD

Eugene Higgins Professor of Molecular Biophysics and Biochemistry and Professor of Molecular, Cellular, and Developmental Biology
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Contact Info

Molecular Biophysics and Biochemistry

PO Box 208114, 266 Whitney Avenue

New Haven, CT 06520-8114

United States

About

Titles

Eugene Higgins Professor of Molecular Biophysics and Biochemistry and Professor of Molecular, Cellular, and Developmental Biology

Biography

Part of the Yale faculty since 2000, Prof. Mark Hochstrasser is the Eugene Higgins Professor of Molecular Biophysics and Biochemistry and also holds appointments in the Department of Molecular, Cellular and Developmental Biology, the Yale Cancer Center, and the School of Medicine’s Biological and Biomedical Sciences Program. He earned his B.A. at Rutgers University and his Ph.D. at the University of California, San Francisco, and conducted postdoctoral research at the Massachusetts Institute of Technology.

He has earned numerous honors for his scientific contributions, including a Young Investigator Award from the Cancer Research Foundation and designation as a Searle Scholar and a Fletcher Scholar. He is an elected Fellow of the American Academy of Arts and Sciences, the American Association for the Advancement of Science, and the Connecticut Academy of Science and Engineering.

Prof. Hochstrasser holds several patents related to his work, which has been published in various scientific and medical journals, including Nature, the Journal of Cell Biology, Cell, the Proceedings of the National Academy of Sciences, Genetics and Nature Cell Biology.

He has been a member of the editorial board of various journals, including Cell, EMBO Journal, Genes & Development, and Molecular Biology of the Cell and has served on several National Institutes of Health study sections. Prof. Hochstrasser has also helped organize numerous international and national scientific conferences and served as an ad hoc reviewer of various research and graduate programs around the country.

Appointments

Education & Training

Postdoctoral Fellow
Massachusetts Institute of Technology (1990)
PhD
University of Califoria-San Francisco (1987)

Research

Overview

Our lab has as its general focus one of the fundamental regulatory systems of eukaryotic cells – the ubiquitin system. Ubiquitin and an array of related molecules (ubiquitin-like proteins or Ubls) such as SUMO are small, highly conserved proteins that are covalently attached to other intracellular proteins, resulting in various functional alterations of these targets. The ubiquitin system has only recently come under close scrutiny, and an extraordinary array of cell regulatory functions is gradually being uncovered. Moreover, many links are now being found between defects in this pathway and human disease, including many cancers, developmental abnormalities, Parkinson’s disease, Alzheimer’s disease, and certain severe forms of mental retardation.

The research in our laboratory can be grouped into three broad and overlapping areas. First, we wish to understand, at a mechanistic and molecular level, how specific proteins are rapidly degraded within eukaryotic cells while most proteins are spared. Such turnover is central to a great variety of regulatory mechanisms, including many of medical relevance. Much of this regulated degradation occurs via the highly conserved ubiquitin-proteasome system. We are currently studying a transmembrane ubiquitin ligase that resides in the nuclear envelope and endoplasmic reticulum. This ligase attaches ubiquitin to both nuclear regulatory proteins and to misfolded membrane proteins degraded at the ER (ER-associated degradation or ERAD). The proteasome is a large, cylindrical machine that fragments proteins into short peptides. Our primary current interest with the proteasome is its mechanism of assembly.

In our second major area of research, we are analyzing the function and dynamics of protein modification by other Ubls. The prototypical example of a protein that is covalently attached to other proteins is ubiquitin, but in recent years, evidence for at least a dozen such systems has come to light. While ubiquitin generally is used to mark its targets for destruction, the consequences of protein ligation to the various Ubls are often poorly understood. The Ubl called SUMO is attached to many proteins in vivo and is crucial for cell-cycle progression. We discovered the first enzymes that can remove SUMO from proteins, causing this protein modification to be highly dynamic. We are trying to understand the functional consequences of SUMO-protein modification, particularly in the cell cycle and chromatin-mediate gene transcription, and to determine the basis of specificity for the SUMO-cleaving proteases. Much of our work is conducted in the yeast Saccharomyces cerevisiae, an organism that permits both facile genetic manipulation and detailed biochemical analysis.

A third, more recent research focus has been on endosymbiotic bacteria that manipulate their eukaryotic hosts by secreting enzymes, including ubiquitin-specific proteases, into the host cell cytoplasm. Wolbachia bacteria alter host processes in ways that increase bacterial inheritance by transmission through the female germline. One such mechanism is called cytoplasmic incompatibility (CI), which has important applications in mosquito-vectored human disease control; we recently discovered the proteins responsible for CI. We also study an unusual ubiquitin-specific protease from Orientia tsutsugamushi, an endosymbiont that causes the mite-vectored disease scrub typhus.

Medical Subject Headings (MeSH)

Biochemistry; Cell Growth Processes; Drosophila; Enzymes; Genetics; Microscopy, Immunoelectron; Molecular Biology; Mutant Chimeric Proteins; Proteasome Endopeptidase Complex; Saccharomyces cerevisiae; Scrub Typhus; Sumoylation; Transcription Factors; Ubiquitin; Wolbachia

Research at a Glance

Yale Co-Authors

Frequent collaborators of Mark Hochstrasser's published research.

Publications

2024

2023

2022

2020

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Contacts

Mailing Address

Molecular Biophysics and Biochemistry

PO Box 208114, 266 Whitney Avenue

New Haven, CT 06520-8114

United States

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