Chromosome instability (CIN) due to genetic perturbation in cancer cells is now widely recognized to be a major predisposing condition in cancer initiation and/or progression. The general objective of this proposal is to identify and characterize the molecular components required for mitotic chromosome transmission fidelity in yeast and to identify cognate components in mammalian species.
The specific aims are: 1). To identify all genes that are mutable to a CIN phenotype, including both essential and nonessential functions. Three independent screens that monitor instability of a chromosomal marker will be used to identify a comprehensive set of proteins that are important for the preservation of genome stability. The corresponding gene sets will be annotated, cross-checked, and compared. 2). To establish genetic interaction maps for CIN genes mutated in human cancer. We will generate comprehensive synthetic lethal genetic interaction maps in yeast for the set of CIN genes altered in human cancer via DNA chip-based screens. RNAi will be used to validate phenotypes in mammalian cells. 3). To establish a resource that systematically cross-references yeast and human CIN genes. Mammalian genes homologous to yeast genes under study will be identified via similarity to yeast protein queries and stored in an annotated searchable database. 4). To investigate the biological functions of NdclO and sumoylation at the kinetochore. Mutations that abrogate sumoylation of NdclO and other kinetochore proteins will be analyzed, and used as starting points for genome-wide screens Further elucidation of the genetic basis of CIN in yeast will provide a mechanistic basis for understanding this process in human cells, and will provide candidate genes for those CIN genes mutated in cancer. Therefore, knowledge gained from this work will provide insight into mechanisms of tumorigenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Janes, K; Symons-Liguori, A M; Jacobson, K A et al. (2016) Identification of A3 adenosine receptor agonists as novel non-narcotic analgesics. Br J Pharmacol 173:1253-67
Oh, Sekyung; Kato, Masaki; Zhang, Chi et al. (2015) A Comparison of Ci/Gli Activity as Regulated by Sufu in Drosophila and Mammalian Hedgehog Response. PLoS One 10:e0135804
Price, Jessica C; Pollock, Lana M; Rudd, Meghan L et al. (2014) Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A. PLoS One 8:e63313
O'Donnell, Kathryn A; An, Wenfeng; Schrum, Christina T et al. (2013) Controlled insertional mutagenesis using a LINE-1 (ORFeus) gene-trap mouse model. Proc Natl Acad Sci U S A 110:E2706-13
Newman, Robert H; Hu, Jianfei; Rho, Hee-Sool et al. (2013) Construction of human activity-based phosphorylation networks. Mol Syst Biol 9:655
Gnanakkan, Veena P; Jaffe, Andrew E; Dai, Lixin et al. (2013) TE-array--a high throughput tool to study transposon transcription. BMC Genomics 14:869
Rybanska-Spaeder, Ivana; Reynolds, Taylor L; Chou, Jeremy et al. (2013) 53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation. Mol Cancer Res 11:1223-34
Le Gallo, Matthieu; O'Hara, Andrea J; Rudd, Meghan L et al. (2012) Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet 44:1310-5
O'Donnell, Kathryn A; Keng, Vincent W; York, Brian et al. (2012) A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer. Proc Natl Acad Sci U S A 109:E1377-86
Burns, Kathleen H; Boeke, Jef D (2012) Human transposon tectonics. Cell 149:740-52

Showing the most recent 10 out of 246 publications