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Title: Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?

Abstract

Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of radiation-induced thymic lymphoma is characterized by a lengthy 'pre-lymphoma' period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of radiation-induced DNA methylation changes in the radiation carcinogenesis target organ-thymus, and non-target organ-muscle. This study is the first report on the radiation-induced epigenetic changes in radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irradiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irradiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure.more » In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the radiation-target tissue, even though DNA damage resulting from initial genotoxic radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of radiation-related pathologies. The possible role of radiation-induced DNA hypomethylation in radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.« less

Authors:
 [1];  [2];  [3]
  1. Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, Alta., T1K 3M4 (Canada)
  2. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)
  3. Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, Alta., T1K 3M4 (Canada). E-mail: olga.kovalchuk@uleth.ca
Publication Date:
OSTI Identifier:
20713443
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 337; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2005.09.084; PII: S0006-291X(05)02049-8; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; BIOLOGICAL RADIATION EFFECTS; DNA; ETIOLOGY; GENES; LEUKEMIA; LEUKEMOGENESIS; LYMPHOMAS; METHYLATION; MICE; MUSCLES; STRAND BREAKS; THYMUS; WHOLE-BODY IRRADIATION

Citation Formats

Koturbash, Igor, Pogribny, Igor, and Kovalchuk, Olga. Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?. United States: N. p., 2005. Web. doi:10.1016/j.bbrc.2005.09.084.
Koturbash, Igor, Pogribny, Igor, & Kovalchuk, Olga. Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?. United States. doi:10.1016/j.bbrc.2005.09.084.
Koturbash, Igor, Pogribny, Igor, and Kovalchuk, Olga. Fri . "Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?". United States. doi:10.1016/j.bbrc.2005.09.084.
@article{osti_20713443,
title = {Stable loss of global DNA methylation in the radiation-target tissue-A possible mechanism contributing to radiation carcinogenesis?},
author = {Koturbash, Igor and Pogribny, Igor and Kovalchuk, Olga},
abstractNote = {Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of radiation-induced thymic lymphoma is characterized by a lengthy 'pre-lymphoma' period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of radiation-induced DNA methylation changes in the radiation carcinogenesis target organ-thymus, and non-target organ-muscle. This study is the first report on the radiation-induced epigenetic changes in radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irradiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irradiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure. In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the radiation-target tissue, even though DNA damage resulting from initial genotoxic radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of radiation-related pathologies. The possible role of radiation-induced DNA hypomethylation in radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.},
doi = {10.1016/j.bbrc.2005.09.084},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 337,
place = {United States},
year = {Fri Nov 18 00:00:00 EST 2005},
month = {Fri Nov 18 00:00:00 EST 2005}
}