Gross chromosomal rearrangements (GCRs) have been identified as mutations that underlie many genetic diseases, including cancer. GCRs also result from the increased genome instability seen in many cancers, which may represent a type of mutator phenotype. Inherited cancer susceptibility syndromes have also been identified that result from genetic defects that cause genome instability in model systems, although whether similar defects cause genome instability and drive the development of sporadic cancers is not clear. While DNA metabolism pathways related to genome instability have been intensely studied, a comprehensive understanding of the pathways and mechanisms that prevent genome instability is not available. Understanding these mechanisms and pathways will impact on human health for several reasons: 1) Identifying the genes that suppress GCRs will provide a basis for understanding the origin of genome instability in cancer;and 2) Genome instability has been proposed as a therapeutic target in cancer and understanding the pathways that suppress genome instability will provide a rational basis for the development of new therapeutic approaches. The goal of this proposal is to use Saccharomyces cerevisiae as a model system to identify the genes and pathways that suppress GCRs. Key related goals are to identify the types of chromosomal features and mechanisms that contribute to genome instability and identify human genes in which defects cause genome instability in cancer. The proposed work will build on insights obtained using previously developed quantitative systems for studying the formation of GCRs in S. cerevisiae. The following lines of experimentation will be carried out: 1) Robotic-based genetic analysis of a bioinformatics-derived set of enriched candidate genes as well as hypomorphic alleles of essential genes including high-density genetic genetic interaction analysis will be performed to identify the genetic network that suppress different kinds of GCRs;2) Genetic studies will be performed to probe the genome for different genomic features that promote GCRs and identify mechanisms that specifically suppress or promote GCRs mediated by these features;3) The mechanistic features of some of the pathways that suppress GCRs will be investigated, initially focusing on chromatin remodeling and modification factors and the CDC73 gene whose human homologue is a tumor suppressor gene;and 4) Human homologues of the S. cerevisiae GCR suppressing genes will be used to mine available cancer genomics data sets to identify genes in which defects cause genome instability in cancer. These studies will provide a comprehensive picture of the pathways and mechanisms that prevent GCRs and provide insights into the origin of genome instability in cancer.

Public Health Relevance

Inherited defects in genes that suppress genome instability cause different inherited cancer susceptibility syndromes and genome instability is seen in many types of sporadic human cancer. This project will identify the genes and pathways that suppress genome instability and elucidate mechanisms by which genome instability is prevented. These insights will facilitate evaluating the basis for genome instability in cancer and lead to new tool for cancer diagnostics and the development of new therapeutic approaches.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Janes, Daniel E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ludwig Institute for Cancer Research Ltd
La Jolla
United States
Zip Code
de Souza, Jorge E S; Fonseca, André F; Valieris, Renan et al. (2014) S-score: a scoring system for the identification and prioritization of predicted cancer genes. PLoS One 9:e94147
Allen-Soltero, Stephanie; Martinez, Sandra L; Putnam, Christopher D et al. (2014) A saccharomyces cerevisiae RNase H2 interaction network functions to suppress genome instability. Mol Cell Biol 34:1521-34
Putnam, Christopher D; Pallis, Katielee; Hayes, Tikvah K et al. (2014) DNA repair pathway selection caused by defects in TEL1, SAE2, and de novo telomere addition generates specific chromosomal rearrangement signatures. PLoS Genet 10:e1004277
Jaehnig, Eric J; Kuo, Dwight; Hombauer, Hans et al. (2013) Checkpoint kinases regulate a global network of transcription factors in response to DNA damage. Cell Rep 4:174-88
Albuquerque, Claudio P; Wang, Guoliang; Lee, Nancy S et al. (2013) Distinct SUMO ligases cooperate with Esc2 and Slx5 to suppress duplication-mediated genome rearrangements. PLoS Genet 9:e1003670
Enserink, Jorrit M; Kolodner, Richard D (2012) What makes the engine hum: Rad6, a cell cycle supercharger. Cell Cycle 11:249-52
Chan, Jason E; Kolodner, Richard D (2011) A genetic and structural study of genome rearrangements mediated by high copy repeat Ty1 elements. PLoS Genet 7:e1002089
Zimmermann, Christine; Chymkowitch, Pierre; Eldholm, Vegard et al. (2011) A chemical-genetic screen to unravel the genetic network of CDC28/CDK1 links ubiquitin and Rad6-Bre1 to cell cycle progression. Proc Natl Acad Sci U S A 108:18748-53
Kolodner, Richard D; Cleveland, Don W; Putnam, Christopher D (2011) Cancer. Aneuploidy drives a mutator phenotype in cancer. Science 333:942-3
Wang, Yuxun; Zhang, Weijia; Edelmann, Lisa et al. (2010) Cis lethal genetic interactions attenuate and alter p53 tumorigenesis. Proc Natl Acad Sci U S A 107:5511-5

Showing the most recent 10 out of 72 publications