Genomic Maintenance and Repair

Sunday, October 16, 2005 1:30 PM-3:00 PM Room No. 603
Chair(s): Chen, David; Powell, Simon

(MS006) Chronic low dose radiation exposure profoundly alters DNA and histone methylation in murine thymus.

Koturbash, Igor1, Pogribny, Igor2, Stevenson, Sandie1, Kovalchuk, Olga*,1, 1 Department of Biological Sciences, Lethbridge, AB, Canada2 Division of Biochemical Toxicology, Jefferson, AR, USA

ABSTRACT- Hematopoietic tissue is a well-documented target of radiation carcinogenesis and both acute and fractionated radiation exposure results in a high risk of leukemia and lymphoma. Notwithstanding, the exact mechanisms of radiation-induced leukemia and lymphoma predisposition are still to be uncovered and contributions of both genetic and epigenetic mechanisms in their generation have yet to be defined. Global DNA hypomethylation is a well-known characteristic of cancer cells. Recent studies have also shown that tumors undergo prominent changes in histone methylation, particularly, a substantial loss of tri-methylation of lysine 20 of histone H4 (H4-Lys 20). These losses are now considered a universal marker of malignant transformation. We have explored the effects of acute versus chronic low dose whole body ionizing radiation exposure on DNA and histone methylation using murine thymus as a model. We show that chronic low dose radiation exposure leads to strong and significant genome DNA hypomethylation, which is paralleled by decreased expression of both maintenance (DNMT1) and de novo (DNMT3a and 3b) DNA methyltransferases as well as a pronounced reduction in the expression of methyl-binding proteins MeCP2 and MBD2. For the first time ever we show that chronic irradiation profoundly alters histone H4-Lys 20 methylation patterns. We found that chronic radiation exposure led to a significant loss of tri-methylation of histone H4-Lys 20. The observed epigenetic cganges were paralleled with the increased levels of DNA damage. Taken together, our results demonstrate the involvement of epigenetic alterations such as DNA and histone H4-Lys 20 hypomethylation in the initial steps of low dose radiation-induced genome destabilization leading to cancer predisposition. Thus, the current study opens the door for the further research into the role of epigenetic changes in radiation stress response and carcinogenesis.

Key words: radiation epigenetics, DNA methylation, histone methylation, DNA damage

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2005 RRS