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, 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, and significant chromosomal instability. Chromosomes with this phenotype are common in tumor derived cell lines and in primary tumors. Furthermore, we have found that exposing cells to ionizing radiation generates chromosomes with this phenotype. Our findings support a model in which the chromosomal instability found in tumor cells, and in cells exposed to ionizing radiation, stems from a defect in the replication timing of certain chromosomal rearrangements. Recently, we developed a chromosome engineering strategy that allows us to generate chromosomes with this delayed replication and condensation phenotype in an efficient and reproducible manner. Our findings indicate that ~5% of all random chromosome translocations display this abnormal phenotype. In addition, on certain balanced translocations only one of the derivative chromosomes displays the phenotype, indicating that a cis-acting mechanism is responsible for this abnormal chromosomal phenotype. The primary goal of this proposal is to characterize this cis-acting mechanism that functions to delay the replication timing of entire chromosomes. This proposal utilizes `chromosome engineering'strategies, combined with somatic cell and molecular genetic approaches, to generate and characterize chromosomes with this delayed replication and condensation phenotype. The long-term goal of these studies is to define the molecular mechanisms responsible for chromosomal instability, one of the most common types of genetic instabilities found in cancer cells.

Public Health Relevance

Genetic changes occur in virtually all types of cancers. In addition, the continuously evolving genomes of cancer cells suggest that an underlying genetic instability is present and responsible for these ongoing genetic changes. This proposal utilizes `chromosome engineering', combined with somatic cell and molecular genetic approaches, to characterize one of the mechanisms responsible for genetic instability in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131967-05
Application #
8267102
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2008-07-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$309,964
Indirect Cost
$108,689
Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
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
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