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Principal Investigator: Anderson Ross Frank
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $76,828
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
An organism’s ability to grow, develop, and reproduce are some of the defining characteristics of life. Central to
growth and reproduction of organisms ranging from single-celled baker’s yeast to humans is the ability of a cell
to replicate its genome and accurately divide the genome into two daughter cells. Errors in the replication or
division of the genome can result in genetic changes that cause disease or are lethal to the cell or organism.
Segregation of the genome is accomplished through an intricate series of steps wherein spindle microtubules
must successfully bind sister chromatids and pull one copy of each chromosome into each daughter cell. The
kinetochore, a conserved megadalton protein complex, mediates microtubule attachment to chromosomes.
Although prior work has successfully charted many kinetochore components, as well as key regulatory steps in
kinetochore assembly and function, this process is still incompletely defined. The goal of this proposal is to
understand how post-translational modifications, specifically ubiquitin, contribute to kinetochore assembly and
function in the budding yeast, Saccharomyces cerevisiae. Using a combination of proteomics, yeast genetics,
and biochemistry, I will generate a comprehensive map of kinetochore regulation by the Mub1/Ubr2 E3 ubiquitin
ligase complex (Aim 1) and investigate how a large family of E3 ubiquitin ligases, the cullin-RING ligases,
regulates kinetochore function (Aim 2). Combined, these approaches will allow me to address how ubiquitylation
influences kinetochore function and generate new knowledge surrounding kinetochore regulation. Given the
highly conserved nature of the kinetochore, this work will likely identify principles of kinetochore regulation that
apply to multiple organisms. Understanding these principles could provide insight into the cellular adaptations
that occur in response to pathological changes in chromosome number (aneuploidy), a common feature of
cancer cells. The training facilitated by this fellowship, along with my previous research experiences, will allow
me to develop the skills necessary to become an independent academic investigator, with the long-term goal of
establishing a research program that uses yeast and mammalian systems to study mechanisms of kinetochore
regulation.
Terms: <APF-1><ATP-Dependent Proteolysis Factor 1><Address><Affinity Chromatography><Aminoacetic Acid><Aneuploid><Aneuploidy><Assay><Baker's Yeast><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biochemistry><Biologic Models><Biological Assay><Biological Chemistry><Biological Function><Biological Models><Biological Process><Biology><Brewer's Yeast><Budding Yeast><Cancers><Cell Body><Cell Cycle><Cell Division Cycle><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Chromosome Segregation><Chromosomes><Complex><Cullin Domain Protein><Cullin Family Gene><Cullin Family Protein><Cullin Proteins><Cullins><Disabling><Disease><Disorder><E3 Ligase><E3 Ubiquitin Ligase><Endomycetales><Eukaryotic Cell><Event><Exhibits><Family><Fellowship><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Glycine><Goals><Growth><Growth and Development><Growth and Development function><HMG-20><High Mobility Protein 20><Human><Impairment><In Vitro><Investigators><Kinetochores><Knowledge><Lab Findings><Laboratory Finding><Life><Ligase><Ligase Gene><Macromolecular Protein Complexes><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Micro-tubule><Microtubules><Mitotic spindle><Model System><Modern Man><Molecular Interaction><Multiprotein Complexes><Mutation><Nature><Organism><Pathologic><Position><Positioning Attribute><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Process><Protein Modification><Proteins><Proteomics><Quality Control><Regulation><Reproduction><Research><Research Personnel><Researchers><Role><S cerevisiae><S. cerevisiae><Saccharomyces cerevisiae><Saccharomycetales><Series><Sister Chromatid><Site><Subcellular Process><Synthetases><System><Tissue Growth><Training><Transcription Factor Proto-Oncogene><Transcription factor genes><Ubiquitin><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitin Like Proteins><Ubiquitin Protein Ligase><Ubiquitin family><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Work><Yeasts><affinity purification><cancer cell><chromosome division><chromosome number abnormality><chromosome replication><daughter cell><entire genome><experience><full genome><genome mutation><genome sequencing><in vivo><insight><living system><malignancy><mechanical force><member><method development><mutant><neoplasm/cancer><novel><ontogeny><particle><programs><protein complex><response><scaffold><scaffolding><segregation><skills><social role><synthetic lethal interaction><temperature sensitive mutant><transcription factor><ubiquitin ligase><ubiquitin-protein ligase><whole genome><yeast genetics>