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Nat Chem. 2014 Dec;6(12):1049-55. doi: 10.1038/nchem.2064. Epub 2014 Sep 21.

5-Hydroxymethylcytosine is a predominantly stable DNA modification.

Author information

1
1] Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK [2] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
2
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
3
1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK [2] Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.

Abstract

5-Hydroxymethylcytosine (hmC) is an oxidation product of 5-methylcytosine which is present in the deoxyribonucleic acid (DNA) of most mammalian cells. Reduction of hmC levels in DNA is a hallmark of cancers. Elucidating the dynamics of this oxidation reaction and the lifetime of hmC in DNA is fundamental to understanding hmC function. Using stable isotope labelling of cytosine derivatives in the DNA of mammalian cells and ultrasensitive tandem liquid-chromatography mass spectrometry, we show that the majority of hmC is a stable modification, as opposed to a transient intermediate. In contrast with DNA methylation, which occurs immediately during replication, hmC forms slowly during the first 30 hours following DNA synthesis. Isotopic labelling of DNA in mouse tissues confirmed the stability of hmC in vivo and demonstrated a relationship between global levels of hmC and cell proliferation. These insights have important implications for understanding the states of chemically modified DNA bases in health and disease.

PMID:
25411882
PMCID:
PMC4382525
DOI:
10.1038/nchem.2064
[Indexed for MEDLINE]
Free PMC Article

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