Graduate Studies Faculty
Mathew Thayer, PhD
Programs:Biochemistry & Molecular Biology
Molecular & Medical Genetics
Neuroscience Graduate Program
Program in Molecular & Cellular Biosciences
Research Interests:Chromosome Structure Genome stability cell cycle checkpoints DNA replication; cellular; medical » PubMed Listing
Preceptor RotationsDr. Thayer has not indicated availability for preceptor rotations at this time.
Faculty MentorshipDr. Thayer has not indicated availability as a mentor at this time.
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.
Kevin S. Breger, Leslie Smith, Mitchell S. Turker, and Mathew J. Thayer. (2004). Ionizing Radiation Induces Frequent Translocations with Delayed Replication and Condensation. Cancer Research, 64, 8231–38.
David Kuninger, Daniel Stauffer, Siavash Eftekhari, Elizabeth Wilson, Mathew Thayer, and Peter Rotwein. (2004). Gene disruption by regulated siRNA expression using a two-adenovirus system. Human Gene Therapy, 15:1287-1292.
Macpartlin M, Zeng SX, Lee H, Stauffer D, Jin Y, Thayer M, Lu H. p300 regulates p63 transcriptional activity. J Biol Chem. 2005 Jun 17; 280:30604-10.
Breger, K. S., Smith, L. G., and Thayer, M. J. Engineering Translocations with Delayed Replication Timing: Evidence for cis Control of Replication Timing. (2005). Hum Mol Genet. 14: 2813-27.
Chang, B.H., Smith, L., Huang, J. and Thayer, M. Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability. (2006) Oncogene, Sep 25; [Epub ahead of print].
Stauffer D, Chang B, Huang J, Dunn A, Thayer M. P300/CBP interacts with ATR and is required for the DNA replication checkpoint. 1: J. Biol. Chem. 2007 Jan 31; [Epub ahead of print]
Graduate Education: University of Southern California; Department of Microbiology; Los Angeles, CA; Graduated June, 1988; Doctor of Philosophy in Microbiology; Dr. R.E.K. Fournier, PhD, advisor