DNMTs are required for delayed genome instability caused by radiation.
The ability of ionizing radiation to initiate genomic instability has been harnessed in the clinic where the localized delivery of controlled doses of radiation is used to induce cell death in tumor cells. Though very effective as a therapy, tumor relapse can occur in vivo and its appearance has been attributed to the radio-resistance of cells with stem cell-like features. The molecular mechanisms underlying these phenomena are unclear but there is evidence suggesting an inverse correlation between radiation-induced genomic instability and global hypomethylation. To further investigate the relationship between DNA hypomethylation, radiosensitivity and genomic stability in stem-like cells we have studied mouse embryonic stem cells containing differing levels of DNA methylation due to the presence or absence of DNA methyltransferases. Unexpectedly, we found that global levels of methylation do not determine radiosensitivity. In particular, radiation-induced delayed genomic instability was observed at the Hprt gene locus only in wild-type cells. Furthermore, absence of Dnmt1 resulted in a 10-fold increase in de novo Hprt mutation rate, which was unaltered by radiation. Our data indicate that functional DNMTs are required for radiation-induced genomic instability, and that individual DNMTs play distinct roles in genome stability. We propose that DNMTS may contribute to the acquirement of radio-resistance in stem-like cells.
Department of Genetics, University of Leicester, Leicester, UK.
Christine A
CA
Armstrong
George D
GD
Jones
Rhona
R
Anderson
Pooja
P
Iyer
Deepan
D
Narayanan
Jatinderpal
J
Sandhu
Rajinder
R
Singh
Christopher J
CJ
Talbot
Cristina
C
Tufarelli
D000818:Animals; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation / Q000235:genetics / Q000528:radiation effects; D053595:Embryonic Stem Cells / Q000528:radiation effects; D042822:Genomic Instability / Q000235:genetics / Q000528:radiation effects*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D051379:Mice; D059645:Mutation Rate; D011836:Radiation Tolerance
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D007041:Hypoxanthine Phosphoribosyltransferase