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BLM Is a Suppressor of DNA Recombination

Straughen, Joel E.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1022269717

Abstract Details

2002, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry and Microbiology.
Bloom’s syndrome (BS) is a rare, recessive chromosome breakage disorder characterized by small stature, sun sensitivity, facial erythema, immunodeficiency, female subfertility, male infertility, and a predisposition to a variety of cancers. When this body of work was started, the gene for Bloom’s syndrome (BLM) had yet to be identified. This work presents characterization of the genomic region at BLM and the identification of BLM. With the cloning of the gene, the answers to a number of questions could be investigated. Additional chapters present data that demonstrate that increased genomic instability and recombination are the result of loss of function of the Bloom’s syndrome gene product. Somatic cells from BS individuals are characterized by a high frequency of chromatid exchanges both between and within chromosomes, as well as by a high mutation rate at specific loci. DNAs from BS and normal clonal cell lines were first examined for alterations at microsatellite repeat loci. Alterations in size microsatellite repeats were observed at a 10-fold increase in frequency in BS clones compared to normal clones. A contiguous representation of 2-Mb region that contains the BLM gene was generated. YAC and P1 clones from the region were identified and ordered using genetic markers in the region along with newly developed sequence tagged sites from radiation-reduced hybrids, polymorphic dinucleotide repeat loci, and end-sequences of YACs and P1s. The physical map, and DNA markers derived from it, was instrumental in identifying BLM. With the gene identified, the genomic structure was determined and a rapid DNA screening test was developed for the identification of Blm Ash, the most common mutation in BS. To determine whether BLM can suppress recombination we over-expressed BLM in separate cell lines capable of identifying recombination or frameshift events. However, no significant difference was noted between cells transfected with BLM and those transfected with vector alone. Finally, we established a mouse model of BS using homologous recombination to disrupt mouse Blm. Genotyping offspring from heterozygous parents did not identify any offspring homozygous for the knockout allele, suggesting embryonic lethal phenotype. In long-term studies, heterozygosity for Blm increases tumor formation compared to wild-type littermates.
Dr. Joanna Groden (Advisor)
140 p.
Bloom's Syndrome; recombination; cancer

Recommended Citations

Citations

  • Straughen, J. E. (2002). BLM Is a Suppressor of DNA Recombination [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1022269717

    APA Style (7th edition)

  • Straughen, Joel. BLM Is a Suppressor of DNA Recombination. 2002. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1022269717.

    MLA Style (8th edition)

  • Straughen, Joel. "BLM Is a Suppressor of DNA Recombination." Doctoral dissertation, University of Cincinnati, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1022269717

    Chicago Manual of Style (17th edition)

ucin1022269717
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© 2002, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.