Item Details

abstract

Cancer development is often initiated by various genetic abnormalities including chromosomal translocations which require DNA breakage. These DNA breaks can occur through exogeneous chemical exposures and/or at regions particularly susceptible to breakage termed “common fragile sites (CFS)”. To test the hypothesis that fragile site breakage underlies the formation of chromosomal rearrangements, we focused on RET/PTC rearrangements in papillary thyroid carcinoma. All genes participating in the two most common types of RET/PTC rearrangements, RET/PTC1 and RET/PTC3, are located within common fragile sites. Fragile sites are sensitive to a variety of environmental chemicals and chemotherapeutic drugs and we have shown that treatment of human thyroid cells with laboratory fragile site-inducing chemicals can cause the formation of RET/PTC rearrangement. Here, we demonstrate that treatment with non-cytotoxic levels of environmental chemicals, benzene and diethylnitrosamine, and chemotherapeutic agents, etoposide and doxorubicin, generate significant DNA breakage within RET at levels similar to those generated by laboratory fragile site-inducing chemicals. These results suggest the role of long-term exposure to these chemicals in the generation of RET/PTC rearrangements. DNA topoisomerases I and II maintain structural integrity by recognizing and cleaving DNA secondary structures such as those at fragile sites. Co-treatment of human thyroid cells with APH and topoisomerase inhibitors significantly altered APH-induced breakage within RET demonstrating their involvement in initiating APH-induced breakage at RET.

subject

Benzene

Cancer

DNA break

RET/PTC

Thyroid

Topoisomerase

contributor

Lehman, Christine Lehman (author)

Wang, Yuh-Hwa (committee chair)

Hollis, Thomas (committee member)

Miller, Mark (committee member)

Ornelles, David (committee member)

Pardee, Timothy (committee member)

date

2016-05-21T08:35:41Z (accessioned)

2018-05-20T08:30:11Z (available)

2016 (issued)

degree

Cancer Biology (discipline)

embargo

2018-05-20 (terms)

identifier

http://hdl.handle.net/10339/59288 (uri)

language

en (iso)

publisher

Wake Forest University

title

DNA FRAGILE SITE BREAKAGE AS A MEASURE OF CHEMICAL EXPOSURE AND PREDICTOR OF THE SUSCEPTIBILITY TO FORM CHROMOSOMAL REARRANGEMENTS

type

Dissertation