Karen Yuen

KAREN WING YEE YUEN- PhD DEFENSE

“Identification and Characterization of Chromosome Instability Mutants in the Yeast Saccharomyces cerevisiae and Implications to Human Cancer”

B.Sc. (Hons.), Simon Fraser University, 2001
Friday, December 15, 2006, 12:30 pm Room 200, Graduate Student Centre

Karen Yuen- PhD Defense program- pdf

SUPERVISORY COMMITTEE

Dr. Philip Hieter (Medical Genetics)

Dr. Carolyn Brown (Medical Genetics)

Dr. Elizabeth Conibear (Medical Genetics)

Dr. Ann Rose (Medical Genetics)

EXAMINING COMMITTEE

Chair: Dr. Grant Mauk (Biochemistry and Molecular Biology)
Supervisory Committee: Dr. Philip Hieter, Research Supervisor (Medical Genetics), Dr. Carolyn Brown (Medical Genetics), Dr. Elizabeth Conibear (Medical Genetics)
University Examiners: Dr. Wendy Robinson (Medical Genetics), Dr. Ralph Durand (Pathology and Laboratory Medicine)
External Examiner: Dr. Guri Nina Giaever. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON

ABSTRACT

Chromosome instability (CIN) is a hallmark of cancers and may contribute to tumorigenesis. Many genes involved in maintaining chromosome stability are conserved in eukaryotes, and some are mutated in cancers. The goal of this thesis is to use Saccharomyces cerevisiae as a model to identify and characterize genes important for chromosome maintenance, investigate the relevance of CIN to cancer, and develop a strategy to identify candidate therapeutic target genes for selective killing of cancer cells. To systematically identify genes important for chromosome stability, non- essential gene deletion yeast mutants were examined using 3 complementary CIN assays. The chromosome transmission fidelity assay monitors loss of an artificial chromosome. The bimater assay monitors loss of heterozygosity at the mating type locus in homozygous diploid deletion mutants. The a-like faker assay detects loss of the MATα mating type locus in haploid deletion mutants. 293 CIN mutants were identified, including genes functioning in the chromosome or cell cycle, and genes not clearly implicated in chromosome maintenance, such as MMS22, MMS1, RTT101 and RTT107. Phenotypic, genetic and biochemical analyses of these 4 gene products indicate that they function in double strand break repair. They may form a ubiquitin ligase complex that regulates the level of some proteins, including Mms22p itself, during DNA damage response. Human homologues of 10 yeast CIN genes identified were previously shown to be mutated in cancers, suggesting that other human homologues are candidate cancer genes. 101 human homologues of yeast CIN genes were sequenced in a panel of colorectal cancers, identifying 20 somatic mutations in 8 genes. In particular, 17 mutations were found in 5 genes involved in sister chromatid cohesion. Further functional studies should reveal whether mutations in cohesion genes contribute to CIN in cancers.
While CIN mutations may contribute to cancer, CIN cancer cells may become inviable when combined with another non-essential mutation, providing the basis for cancer cell-specific therapy. Mutations in CTF4, CTF18, and DCC1 in yeast cause synthetic lethality when combined with mutations in various CIN genes whose human homologues are mutated in cancers. Such analyses in yeast can propose potential drug targets in human for cancer therapy.

PUBLICATIONS

Yuen K*, Warren C*, Chen O, Kwok T, Hieter P, and Spencer F (*These authors contributed equally to this work). Systematic Genome Instability Screens in Yeast Identify Candidate Cancer Genes. Being reviewed by Proc Natl Acad Sci U S A.

Yuen K*, Montpetit B*, Hieter P, 2005 (*These authors contributed equally to this work). The kinetochore and cancer: what's the connection? Current Opinion in Cell Biology. 17(6):576-82.

Measday V*, Baetz K*, Guzzo J, Yuen K, Kwok T, Sheikh B, Ding H, Ueta R, Hoac T, Cheng B, Pot I, Tong A, Yamaguchi-Iwai Y, Boone C, Hieter P, Andrews B, 2005 (*These authors contributed equally to this work). Systematic yeast synthetic lethal and synthetic dosage lethal screens identify genes required for chromosome segregation. Proc Natl Acad Sci U S A. 102(39):13956-61.

PRESENTATIONS

Systematic Genome Instability Screens in Yeast Identify Candidate Cancer Genes. Poster presented at the Yeast Chromosome Structure, Replication & Segregation FASEB Conference, Indian Wells, CA, USA, June, 2006.

Systematic Genome Instability Screens in Yeast Identify Candidate Cancer Genes. Poster presented at the Yeast Cell Biology Meeting, Cold Spring Harbor, NY, USA, August, 2005.

Genome-wide Screens for Non-essential Chromosome Instability Mutants in S. cerevisiae. Poster presented at the Yeast Genetics and Molecular Biology Meeting, University of Washington, Seattle, WA, USA, July, 2004.

Genomic Approaches to Identify Chromosome Transmission Fidelity Mutants in the Budding Yeast Saccharomyces cerevisiae. Talk given at Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, TN, USA, August, 2003.

A Genomic Screen for Non-essential Chromosome Transmission Fidelity Mutants. Poster presented at the Yeast Cell Biology Meeting, Cold Spring Harbor, NY, USA, August, 2003.

Genomic Approaches to Identify Chromosome Transmission Fidelity Mutants in the Budding Yeast Saccharomyces cerevisiae. Talk given at Institute of Genetic Medicine, Johns Hopkins University of Medicine, Baltimore, MD, USA, April, 2003

AWARDS

2004 – 2006 NSERC Postgraduate Scholarship – PGSD
2004 – UBC Albert B and Mary Steiner Summer Research Award
2003 – 2004  UBC Graduate Fellowship
2001 – 2003 NSERC Postgraduate Scholarship – PGSA
2001 – 2002 UBC Faculty of Medicine Grant Supplement Award

GRADUATE STUDIES

Field of Study: Chromosome and Cancer Biology

COURSES
MEDG520 Advanced Human Molecular Genetics, E. Simpson
MEDG521 Biology and Genetics of Neoplasm, F. Takei
MEDG530 Advanced Human Genetics, J. Friedman
MEDG540 Medical Genetics Seminar, F. Dill / C. Brown
MEDG545 Current Topics in Medical Genetics, W. Robinson
 
Karen Yuen- PhD Defense program- pdf