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

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.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2016

Author dc:creator

• Lehman, Christine Lehman

• Benzene

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/59288

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/59288