Whole genome duplications or polyploidy are frequent in biology but their physiological significance is poorly understood. Polyploidy occurs during development, cellular stress, tissue damage, cancer, and evolution. Although polyploidy likely confers some short-term advantages, it has costs. Most notably, in many situations newly formed polyploid cells appear to be genetically unstable. In this proposal we will take molecular genetic approaches to define the mechanisms leading to genetic instability in polyploid cells. In the last funding period we have developed several cell systems that uniquely position this laboratory to attack this question. We developed a breast cancer animal model that provided the first direct test of the longstanding hypothesis that passing through an unstable tetraploid intermediate can promote tumorigenesis. Using budding yeast, we discovered a genetic phenomenon called ploidy-specific lethality that provides an experimental avenue to define underlying mechanisms of genetic instability in polyploidy cells: certain genes are not required for viability in haploid or diploid cells but become essential in polyploidy cells. We conducted a genome-wide screen and found a small and specific subset of genes (39/3740 screened) that when compromised result in ploidy-specific lethality. Strikingly, almost all of these genes affect aspects of genetic stability. Based on these preliminary results, we will take complementary approaches in both yeast and mammalian cells to define how polyploidy affects genetic stability. We propose experiments with the following aims:
Aim 1. How does tetraploidy promote whole chromosome aneuploidy in yeast? Aim 2. How does polyploidy affect recombination and the ability of cells to acquire growth-promoting mutations? Aim 3. What mechanisms lead to chromosomal aberrations in tetraploid mammalian cells? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
9R01GM083299-11
Application #
7320466
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Deatherage, James F
Project Start
1997-05-01
Project End
2011-05-31
Budget Start
2007-08-01
Budget End
2008-05-31
Support Year
11
Fiscal Year
2007
Total Cost
$393,300
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Li, Hubo; Mar, Brenton G; Zhang, Huadi et al. (2017) The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. Blood 129:497-508
Gordon, D J; Motwani, M; Pellman, D (2016) Modeling the initiation of Ewing sarcoma tumorigenesis in differentiating human embryonic stem cells. Oncogene 35:3092-102
Zhang, Cheng-Zhong; Spektor, Alexander; Cornils, Hauke et al. (2015) Chromothripsis from DNA damage in micronuclei. Nature 522:179-84
Leibowitz, Mitchell L; Zhang, Cheng-Zhong; Pellman, David (2015) Chromothripsis: A New Mechanism for Rapid Karyotype Evolution. Annu Rev Genet 49:183-211
Ganem, Neil J; Cornils, Hauke; Chiu, Shang-Yi et al. (2014) Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell 158:833-848
Godinho, Susana A; Picone, Remigio; Burute, Mithila et al. (2014) Oncogene-like induction of cellular invasion from centrosome amplification. Nature 510:167-71
Zhang, Cheng-Zhong; Leibowitz, Mitchell L; Pellman, David (2013) Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev 27:2513-30
Gordon, David J; Resio, Benjamin; Pellman, David (2012) Causes and consequences of aneuploidy in cancer. Nat Rev Genet 13:189-203
Crasta, Karen; Ganem, Neil J; Dagher, Regina et al. (2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature 482:53-8
Carter, Scott L; Cibulskis, Kristian; Helman, Elena et al. (2012) Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 30:413-21

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