OHSU

Mathew Thayer, Ph.D.

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503 494-2450

Background

Genetic instability occurs in cancer cells at distinct levels. In most cancers, the instability occurs at the chromosome level, resulting in gains or losses of whole chromosomes or large portions of chromosomes. In contrast to standard molecular genetic approaches, somatic cell genetics offers the ability to ascertain the functional significance of complex genetic lesions, such as gene amplifications, duplications, inversions, or translocations, which occur frequently in tumor cells. By utilizing a combined somatic cell and molecular genetic approach, my laboratory has recently characterized a new type of chromosomal abnormality that occurs with a subset of chromosomal alterations (Smith et al., PNAS 98:13300-05, 2001). We found that four different translocation chromosomes display a delay in mitotic chromosome condensation (DMC) that is associated with a delay in the mitosis-specific phosphorylation of histone H3. Furthermore, this DMC phenotype is preceded by a delay in chromosome replication timing (DRT) that is characterized by a delay in the initiation as well as the completion of DNA synthesis. In addition, chromosomes with this phenotype participate in numerous secondary translocations and rearrangements, indicating that these chromosomes display chromosomal instability. Chromosomes with this phenotype are common in tumor cell lines and primary tumor samples. Furthermore, chromosomes with DMC/DRT can be generated by ionizing radiation. Our findings suggest that certain chromosomal alterations cause a significant delay in replication timing of the entire chromosome that subsequently results in delayed mitotic chromosome condensation and ultimately in chromosomal instability. The primary goal of this research is to determine the genetic basis for the DMC/DRT phenotype. We are considering two possibilities to explain why certain chromosome rearrangements display DMC/DRT. First, because all of the translocations that display DMC/DRT involve deletion and/or rearrangement of the affected chromosomes, it is possible that deletion or mutation of a cis element that normally establishes early replication timing has occurred. Deletion of this element would then result in delayed replication of the entire chromosome. Second, because the chromosomes with DMC/DRT involve translocations or rearrangements in or near their centromeres, it is possible that this type of rearrangement actively interferes with normal replication timing by an unknown mechanism. We are currently using chromosome engineering strategies, combined with somatic cell and molecular genetics, to generate and characterize chromosomes with DMC/DRT.


Summary of Current Research

We recently found that exposing cells to radiation can also result in this abnormal chromosome duplication problem. Chromosome duplication is central to cell division and is tightly regulated when cells divide. Our work indicates that these chromosomes that duplicate at the wrong time are prone to break during cell division, and as a result become extensively rearranged. The consequence to the cell of having one of these chromosomes is that new chromosome alterations occur quite frequently, thereby resulting in the generation of many new mutations. Therefore, our work has identified a process that occurs in both cancer cells and in cells exposed to radiation, and therefore can explain the genetic instability that occurs in both cancer cells and in cells exposed to radiation. In our most recent work, we have developed a “chromosome engineering” system that allows us to create chromosomes with this duplication problem in a controlled manner


Selected Publications

"Asynchronous Replication, Mono-Allelic Expression, and Long Range Cis-Effects of ASAR6," PLoS Genetics (Vol: 9, Issue: 4, ) - 2013

"DNA replication timing, genome stability and cancer. Late and/or delayed DNA replication timing is associated with increased genomic instability.," Seminars in Cancer Biology (Vol: 23, Issue: 2, Page 80-89) - 2013

"Chromosome replicating timing combined with fluorescent In situ hybridization," Journal of Visualized Experiments ( Issue: 70, ) - 2012

"Chromosome replicating timing combined with fluorescent In situ hybridization," Journal of Visualized Experiments ( Issue: 69, ) - 2012

"Chromosome replicating timing combined with fluorescent in situ hybridization.," Journal of visualized experiments : JoVE ( Issue: 70, Page e4400) - 2012

 

Contact

  Email Mathew Thayer

503 494-2447

Memberships & Associations

Biochemistry & Molecular Biology
Molecular & Medical Genetics
Neuroscience Graduate Program
Program in Molecular & Cellular Biosciences