Cancer cells differ from their normal cellular counterparts in many important characteristics, including loss of differentiation, increased genomic instability, and decreased drug sensitivity. Not surprisingly, genetic alterations occur in most, if not all cancer cells, and are thought to lie at the heart of these phenotypic alterations. Furthermore, an underlying genetic instability is thought to be required to generate the multiple genetic changes that occur in cancer cells. My laboratory uses somatic cell and molecular genetics to identify and characterize genetic alterations found in tumor cells that induce abnormal cellular phenotypes. By utilizing this approach, my lab has identified a previously unknown chromosomal abnormality that is associated with certain chromosomal rearrangements. This chromosomal phenotype is characterized by a delay in mitotic chromosome condensation, a delay in the chromosome replication timing, over-expression of the replication checkpoint kinase ATR, and significant chromosomal instability. Chromosomes with this phenotype are common in tumor derived cell lines and in primary tumors. Furthermore, we have found that chromosomes with this phenotype activate the DNA replication checkpoint (S-M phase checkpoint). Our findings support a model in which the chromosomal instability found in tumor cells stems from a defect in the replication timing of certain chromosomal rearrangements. The experiments described in this proposal are designed to characterize the cellular response to these abnormal chromosomes. This proposal is designed to: 1) determine the mechanisms by which stalled or delayed DNA replication results in ATR over-expression; 2) characterize the role that the DNA replication checkpoint plays in the DRT/DMC phenotype, and 3) determine if chromosomes with DRT/DMC activate the mitotic spindle checkpoints. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104693-04
Application #
7228068
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Pelroy, Richard
Project Start
2004-07-26
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$264,158
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Donley, Nathan; Stoffregen, Eric P; Smith, Leslie et al. (2013) Asynchronous replication, mono-allelic expression, and long range Cis-effects of ASAR6. PLoS Genet 9:e1003423
Donley, Nathan; Thayer, Mathew J (2013) DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability. Semin Cancer Biol 23:80-9
Stoffregen, Eric P; Donley, Nathan; Stauffer, Daniel et al. (2011) An autosomal locus that controls chromosome-wide replication timing and mono-allelic expression. Hum Mol Genet 20:2366-78
Stauffer, Daniel; Chang, Bill; Huang, Jing et al. (2007) p300/CREB-binding protein interacts with ATR and is required for the DNA replication checkpoint. J Biol Chem 282:9678-87
Chang, B H; Smith, L; Huang, J et al. (2007) Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability. Oncogene 26:1852-61
Breger, Kevin S; Smith, Leslie; Thayer, Mathew J (2005) Engineering translocations with delayed replication: evidence for cis control of chromosome replication timing. Hum Mol Genet 14:2813-27