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dc.contributor.advisorAngelika Amon.en_US
dc.contributor.authorBrennan, Christopher M.,Ph.D.Massachusetts Institute of Technology.en_US
dc.contributor.otherMassachusetts Institute of Technology. Department of Biology.en_US
dc.date.accessioned2020-02-10T21:36:50Z
dc.date.available2020-02-10T21:36:50Z
dc.date.copyright2019en_US
dc.date.issued2019en_US
dc.identifier.urihttps://hdl.handle.net/1721.1/123701
dc.descriptionThis electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.en_US
dc.descriptionThesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2019en_US
dc.descriptionCataloged from student-submitted PDF version of thesis.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractAneuploidy, or an incorrect number of chromosomes, is caused by errors in chromosome segregation during cell division. Because genes are expressed in accordance with their copy number, aneuploidy simultaneously alters the gene dosage of hundreds to thousands of genes. The outcome is an imbalanced proteome, which has a negative impact on cellular physiology and places intense demand on the protein quality control system of the cell to effectively fold and/or degrade proteins. Aneuploidy further represents an ideal model for studying how cells cope with imbalances in their proteome as it allows for interrogation of the fate of hundreds to thousands of imbalanced proteins simultaneously. Here, we identify protein complex stoichiometry imbalances as a major cause of protein aggregation in aneuploid cells. Subunits of protein complexes encoded on excess chromosomes aggregate in aneuploid cells, which is suppressed when expression of other subunits is coordinately altered. We further show that excess subunits are either degraded or aggregate, a fate that is largely mutually exclusive for individual subunits. We also demonstrate that protein aggregation is nearly as effective as protein degradation at lowering levels of excess proteins. Our study explains why proteotoxic stress is a universal feature of the aneuploid state and reveals protein aggregation as a form of dosage compensation to cope with disproportionate expression of protein complex subunits. This work informs both our comprehension of aneuploid cell physiology, and also provides a more complete understanding of how aneuploid and euploid cells cope with stoichiometric imbalances, namely that protein aggregation can function as protein quality control mechanism in this regard.en_US
dc.description.statementofresponsibilityby Christopher M. Brennan.en_US
dc.format.extent143 pagesen_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsMIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582en_US
dc.subjectBiology.en_US
dc.titleAneuploidy reveals insights into control of protein complex stoichiometryen_US
dc.typeThesisen_US
dc.description.degreePh. D.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.identifier.oclc1138012751en_US
dc.description.collectionPh.D. Massachusetts Institute of Technology, Department of Biologyen_US
dspace.imported2020-02-10T21:36:48Zen_US
mit.thesis.degreeDoctoralen_US
mit.thesis.departmentBioen_US


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