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Mechanisms of alternative telomere elongation in human cancer cells

Gocha, April Renee Sandy
http://rave.ohiolink.edu/etdc/view?acc_num=osu1351190051

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Telomeres are DNA-protein structures that cap the ends of chromosomes and are important modulators of genomic stability. Telomeres shorten with each round of cell division and must be actively maintained in cells with high rates of proliferation, such as cancer cells. Cancer cells can elongate telomeres with the telomerase enzyme or in a telomerase-independent manner termed alternative lengthening of telomeres (ALT). ALT uses recombination to copy telomeric templates to lengthen shortened chromosome ends, although the exact functions and mechanisms of ALT are still loosely defined. While some proteins are essential for ALT, the role of other proteins implicated at the telomeres is still unknown. Due to structural and functional similarities to the BLM helicase, mutated in Bloom syndrome and required for ALT, this work asked whether the WRN helicase, mutated in Werner syndrome, is also required for ALT. Short interfering RNA knockdown of WRN in immortalized human cell lines demonstrates that WRN is necessary for ALT in some, but not all, ALT cell lines. In cells that require WRN for ALT, WRN knockdown results in telomere shortening and a loss of ALT characteristics. The requirement for WRN in ALT correlates with an interaction between WRN and the BRCA1 tumor suppressor. These results imply that ALT cells can use different mechanisms of alternative telomere maintenance and that these mechanisms make use of unique protein complexes. In a more clinical scope, this work also asked whether telomere maintenance mechanisms within human sarcoma tumors, which are known to have a high incidence of ALT, are variable. Both immunohistochemical and biochemical methods were used to evaluate human sarcomas for the presence of telomerase-expressing cells and cells with characteristics of the ALT pathway. This work has shown that ALT and telomerase are not mutually exclusive in some human sarcomas and that some tumors have a high degree of tumor heterogeneity in regards to telomere maintenance, with cells using either mechanism within the tumor. ALT is used by an estimated 15% of human tumors. Therefore, understanding ALT mechanisms will be important for the development of effective therapeutic strategies to inhibit ALT tumors. The clinical use of telomerase inhibitors in recent clinical trials warrants a close inspection of telomere maintenance in human tumors to get true measures of accurate therapeutic responses.
Joanna Groden (Advisor)
Samir Acharya (Committee Member)
Altaf Wani (Committee Member)
Jeffrey Parvin (Committee Member)
139 p.
Biomedical Research
telomere maintenance; telomere; ALT; telomerase; WRN; Werner syndrome; sarcoma

Recommended Citations

Citations

  • Gocha, A. R. S. (2012). Mechanisms of alternative telomere elongation in human cancer cells [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1351190051

    APA Style (7th edition)

  • Gocha, April. Mechanisms of alternative telomere elongation in human cancer cells. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1351190051.

    MLA Style (8th edition)

  • Gocha, April. "Mechanisms of alternative telomere elongation in human cancer cells." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1351190051

    Chicago Manual of Style (17th edition)

osu1351190051
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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.