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Chromosome structure, DNA replication, chromosome translocations in cancer, genomic instability

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.
 

Recent Publications:

1. Breger KS, Smith L, Turker MS, Thayer MJ. Ionizing radiation induces frequent translocations with delayed replication and condensation. Cancer Res. 2004 Nov 15;64(22):8231-8.

2. Guo CS, Degnin C, Fiddler TA, Stauffer D, Thayer MJ. Free Full Text Regulation of MyoD activity and muscle cell differentiation by MDM2, pRb, and Sp1. J Biol Chem. 2003 Jun 20;278(25):22615-22. Epub 2003 Apr 17.

3. Johnson-Pais T, Degnin C, Thayer MJ. Free in PMC pRB induces Sp1 activity by relieving inhibition mediated by MDM2. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2211-6.