{"id":{"repo_id":"wfu","oai_identifier":"oai:wakespace.lib.wfu.edu:10339/59288"},"canonical_url":"https://search.dev.ndltd.org/etd/wfu/oai:wakespace.lib.wfu.edu:10339/59288","repository":{"repo_id":"wfu","name":"Wake Forest University","base_url":"https://wakespace.lib.wfu.edu/oai/request"},"display":{"title":"DNA FRAGILE SITE BREAKAGE AS A MEASURE OF CHEMICAL EXPOSURE AND PREDICTOR OF THE SUSCEPTIBILITY TO FORM CHROMOSOMAL REARRANGEMENTS","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Lehman, Christine Lehman"],"institution":"Wake Forest University","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016","date_published":"2016","updated_at":"2026-07-27T22:01:58Z","subjects":["Benzene"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10339/59288","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Lehman, Christine Lehman"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2016-05-21T08:35:41Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2018-05-20T08:30:11Z"]},{"key":"dc:date.issued","label":"Date","values":["2016"]},{"key":"dc:publisher","label":"Institution","values":["Wake Forest University"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Benzene"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10339/59288"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:title","label":"Title","values":["DNA FRAGILE SITE BREAKAGE AS A MEASURE OF CHEMICAL EXPOSURE AND PREDICTOR OF THE SUSCEPTIBILITY TO FORM CHROMOSOMAL REARRANGEMENTS"]}]}],"canonical_facts":{"dc:creator":["Lehman, Christine Lehman"],"dc:date.accessioned":["2016-05-21T08:35:41Z"],"dc:date.available":["2018-05-20T08:30:11Z"],"dc:date.issued":["2016"],"dc:description.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."],"dc:identifier.uri":["http://hdl.handle.net/10339/59288"],"dc:language.iso":["en"],"dc:publisher":["Wake Forest University"],"dc:subject":["Benzene"],"dc:title":["DNA FRAGILE SITE BREAKAGE AS A MEASURE OF CHEMICAL EXPOSURE AND PREDICTOR OF THE SUSCEPTIBILITY TO FORM CHROMOSOMAL REARRANGEMENTS"],"dc:type":["Dissertation"]},"updated_at":"2026-07-27T22:01:58Z"}