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DNMTs are required for delayed genome instability caused by radiation

Armstrong, Christine A.; Jones, George Tripp; Anderson, Rhona; Iyer, Pooja; Narayanan, Deepan; Sandhu, Jatinderpal; Singh, Rajinder; Talbot, Christopher J.; Tufarelli, Cristina

Authors

Christine A. Armstrong

George Tripp Jones

Rhona Anderson

Pooja Iyer

Deepan Narayanan

Jatinderpal Sandhu

Rajinder Singh

Christopher J. Talbot

Cristina Tufarelli



Abstract

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.

Journal Article Type Article
Publication Date Aug 1, 2012
Journal Epigenetics
Print ISSN 1559-2294
Electronic ISSN 1559-2294
Publisher Taylor & Francis
Peer Reviewed Peer Reviewed
Volume 7
Issue 8
APA6 Citation Armstrong, C. A., Jones, G. T., Anderson, R., Iyer, P., Narayanan, D., Sandhu, J., …Tufarelli, C. (2012). DNMTs are required for delayed genome instability caused by radiation. Epigenetics, 7(8), doi:10.4161/epi.21094
DOI https://doi.org/10.4161/epi.21094
Publisher URL https://www.landesbioscience.com/journals/epigenetics/article/21094/?nocache=610625806
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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