PMID- 16254189
OWN - NLM
STAT- MEDLINE
DCOM- 20060209
LR  - 20220408
IS  - 1541-7786 (Print)
IS  - 1541-7786 (Linking)
VI  - 3
IP  - 10
DP  - 2005 Oct
TI  - Fractionated low-dose radiation exposure leads to accumulation of DNA damage and 
      profound alterations in DNA and histone methylation in the murine thymus.
PG  - 553-61
AB  - Thymus, an important component of hematopoietic tissue, is a well-documented 
      "target" of radiation carcinogenesis. Both acute and fractionated irradiation 
      result in a high risk of leukemia and thymic lymphoma. However, the exact 
      mechanisms underlying radiation-induced predisposition to leukemia and lymphoma 
      are still unknown, and the contributions of genetic and epigenetic mechanisms in 
      particular have yet to be defined. Global DNA hypomethylation is a well-known 
      characteristic of cancer cells. Recent studies have also shown that tumor cells 
      undergo prominent changes in histone methylation, particularly a substantial loss 
      of trimethylation of histone H4-Lys20 and demethylation of genomic DNA. These 
      losses are considered a universal marker of malignant transformation. In the 
      present study, we investigated the effect of low-dose radiation exposure on the 
      accumulation of DNA lesions and alterations of DNA methylation and histone 
      H4-Lys20 trimethylation in the thymus tissue using an in vivo murine model. For 
      the first time, we show that fractionated whole-body application of 0.5 Gy X-ray 
      leads to decrease in histone H4-Lys20 trimethylation in the thymus. The loss of 
      histone H4-Lys20 trimethylation was accompanied by a significant decrease in 
      global DNA methylation as well as the accumulation of DNA damage as monitored by 
      persistence of histone gammaH2AX foci in the thymus tissue of mice exposed to 
      fractionated irradiation. Altered DNA methylation was associated with reduced 
      expression of maintenance (DNMT1) and, to a lesser extent, de novo DNA 
      methyltransferase DNMT3a in exposed animals. Expression of another de novo DNA 
      methyltransferase DNMT3b was decreased only in males. Irradiation also resulted 
      in approximately 20% reduction in the levels of methyl-binding proteins MeCP2 and 
      MBD2. Our results show the involvement of epigenetic alterations in 
      radiation-induced responses in vivo. These changes may play a role in genome 
      destabilization that ultimately leads to cancer.
FAU - Pogribny, Igor
AU  - Pogribny I
AD  - Division of Biochemical Toxicology, National Center for Toxicological Research, 
      Jefferson, Arkansas, USA.
FAU - Koturbash, Igor
AU  - Koturbash I
FAU - Tryndyak, Volodymyr
AU  - Tryndyak V
FAU - Hudson, Darryl
AU  - Hudson D
FAU - Stevenson, Sandie M L
AU  - Stevenson SM
FAU - Sedelnikova, Olga
AU  - Sedelnikova O
FAU - Bonner, William
AU  - Bonner W
FAU - Kovalchuk, Olga
AU  - Kovalchuk O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (Histones)
RN  - 9007-49-2 (DNA)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
SB  - IM
MH  - Animals
MH  - DNA/*radiation effects
MH  - DNA (Cytosine-5-)-Methyltransferases/metabolism
MH  - *DNA Damage
MH  - DNA Methylation/*radiation effects
MH  - Dose Fractionation, Radiation
MH  - Dose-Response Relationship, Radiation
MH  - Female
MH  - Gene Expression
MH  - Histones/*metabolism/*radiation effects
MH  - Male
MH  - Methylation/radiation effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Thymus Gland/enzymology/*radiation effects
MH  - Whole-Body Irradiation
EDAT- 2005/10/29 09:00
MHDA- 2006/02/10 09:00
CRDT- 2005/10/29 09:00
PHST- 2005/10/29 09:00 [pubmed]
PHST- 2006/02/10 09:00 [medline]
PHST- 2005/10/29 09:00 [entrez]
AID - 3/10/553 [pii]
AID - 10.1158/1541-7786.MCR-05-0074 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2005 Oct;3(10):553-61. doi: 10.1158/1541-7786.MCR-05-0074.