Date Available
10-27-2011
Year of Publication
2011
Degree Name
Doctor of Philosophy (PhD)
Document Type
Dissertation
College
Medicine
Department
Microbiology, Immunology, and Molecular Genetics
First Advisor
Dr. Andrew J. Pierce
Abstract
Genomic instability driven by non-allelic homologous recombination (NAHR) provides a realistic mechanism that could account for the numerous chromosomal abnormalities that are hallmarks of cancer. We recently demonstrated that this type of instability could be assayed by analyzing the copy number variation of the human ribosomal RNA gene clusters (rDNA). Further, we found that gene cluster instability (GCI) was present in greater than 50% of the human cancer samples that were tested. Here, data is presented that confirms this phenomenon in the human GAGE gene cluster of those cancer patients. This adds credence to the hypothesis that NAHR could be a driving force for carcinogenesis. This data is followed by experimental results that demonstrate the same gene cluster instability in cultured cells that are deficient for the human BLM protein. Bloom’s Syndrome (BS) results from a genetic mutation that results in the abolition of BLM protein, one of human RecQ helicase. Studies of Bloom’s Syndrome have reported a 10-fold increase in sister chromatid exchanges during mitosis which has primarily been attributed to dysregulated homologous recombination. BS also has a strong predisposition to a broad spectrum of malignancies. Biochemical studies have determined that the BLM protein works in conjunction with TOPOIIIα and RMI1/RMI2 to function as a Holliday Junction dissolvase that suppress inadvertent crossover formation in mitotic cells. Because of the similarities in their biochemical activities it was suggested that another DNA helicase found in E. coli, the RecG DNA translocase, is the functional analog of BLM. RecG shares no sequence homology with BLM but it can complement both the sister chromatid exchange elevation and the gene- cluster instability phenotype caused by BLM deficiency. This indicates that the physiological function of BLM that is responsible for these phenotypes rests somewhere in the shared biochemical activities of these two proteins. These data taken together give new insights into the physiological mechanism of BLM protein and the use of Bloom’s Syndrome as a model for carcinogenesis.
Recommended Citation
Killen, Michael Wayne, "LOSS OF BLOOM SYNDROME PROTEIN CAUSES DESTABILIZATION OF GENOMIC ARCHITECTURE AND IS COMPLEMENTED BY ECTOPIC EXPRESSION OF Escherichia coli RecG IN HUMAN CELLS" (2011). University of Kentucky Doctoral Dissertations. 201.
https://uknowledge.uky.edu/gradschool_diss/201
Included in
Biochemistry Commons, Cell Biology Commons, Genetics Commons
