The long term goal of this study is to understand the molecular basis of genomic instability and its role in cancer. The three aims in this proposal are motivated by our previous study [1] and from a recently published study in mammalian cancer cells. We have used the model organism Saccharomyces cerevislae (budding yeast) to develop a specific chromosome assay system (referred to as the ChrVII system in this proposal). We have previously used this system to identify a novel unstable chromosome site (a fragile site) that when unstable leads to the formation of unstable chromosome intermediates. We have identified roles of key genes in stability of the fragile site, and have developed a working model that explains its instability. In this proposal, we first will continue to identify genes and genetic pathways required to stabilize the specific unstable site, using both a candidate gene and a genome wide genetic screen. Second, we will identify additional genetically unstable sites in the yeast genome, which will lead to an understanding of the multiple chromosomal determinants that cause instability. Third, we will test one hypothesis for why unstable chromosome intermediates are unstable. This one hypothesis is motivated in part by recent observations in cancer cells that suggest to us that unstable chromosomes are common, for unknown but potentially important reasons, in yeast and in mammalian cells (and thus probably in all cell types). Each of these three aims is of interest in cancer research, and each is technically demanding enough that detailed study in all but the most sophisticated model organisms is cumbersome at best. Budding yeast has a sophisticated yet easily manipulated genome, and as such is useful to carry out the experiments proposed that are of general relevance in chromosome biology and cancer. This project will also provide an excellent educational and training vehicle for Native American students in cancer biology, and thus will contribute strongly to the goals of The Partnership for Native American Cancer Prevention to alleviate the unequal burden of cancer among Native Americans.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-SRLB-D)
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University of Arizona
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Huynh, Julie M; Laukaitis, Christina M (2016) Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer. Mol Genet Genomic Med 4:232-6
Bea, J W; Blew, R M; Going, S B et al. (2016) Dual energy X-ray absorptiometry spine scans to determine abdominal fat in postmenopausal women. Am J Hum Biol 28:918-926
Laurila, Kelly; Ingram, Jani C; Briehl, Margaret M et al. (2015) Weaving the Web: Evaluation Strategies to Help Native-American Undergraduate Research Training Programs Navigate Students to Success. CURQ Web 35:4-11
Briehl, Margaret M (2015) Oxygen in human health from life to death--An approach to teaching redox biology and signaling to graduate and medical students. Redox Biol 5:124-39
Trotter 2nd, Robert T; Laurila, Kelly; Alberts, David et al. (2015) A diagnostic evaluation model for complex research partnerships with community engagement: the partnership for Native American Cancer Prevention (NACP) model. Eval Program Plann 48:10-20
Purohit, Rahul; Fritz, Bradley G; The, Juliana et al. (2014) YC-1 binding to the β subunit of soluble guanylyl cyclase overcomes allosteric inhibition by the α subunit. Biochemistry 53:101-14
Karn, Robert C; Chung, Amanda G; Laukaitis, Christina M (2014) Did androgen-binding protein paralogs undergo neo- and/or Subfunctionalization as the Abp gene region expanded in the mouse genome? PLoS One 9:e115454
Gustafson, Heather L; Yao, Song; Goldman, Bryan H et al. (2014) Genetic polymorphisms in oxidative stress-related genes are associated with outcomes following treatment for aggressive B-cell non-Hodgkin lymphoma. Am J Hematol 89:639-45
Karn, Robert C; Laukaitis, Christina M (2014) Selection shaped the evolution of mouse androgen-binding protein (ABP) function and promoted the duplication of Abp genes. Biochem Soc Trans 42:851-60
Briehl, Margaret M; Tome, Margaret E; Wilkinson, Sarah T et al. (2014) Mitochondria and redox homoeostasis as chemotherapeutic targets. Biochem Soc Trans 42:939-44

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