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Archive - Sep 12, 2013

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“Zone in with Zon”—Cytosine, the “Wild Card” Base in Epigenetics

Dr. Gerald Zon’s latest “Zone in with Zon” blog post, dated September 9, 2013, compares the curious chemical biology of cytosine in epigenetics with the “curiouser and curiouser” happenings that Alice discovered after following the White Rabbit down a large rabbit hole. Dr. Zon begins this fascinating treatment by first offering a brief discussion of the basics of epigenetics, particularly the role of 5-methylated cytosine (5mC). Dr. Zon notes that in mammals 5mC is required for allele-specific expression of imprinted genes, transcriptional repression of retrotransposons, and for X chromosome inactivation in females. He also describes “passive” and “active” demethylation. He noted that so-called 5mC “erasers” have been sought for a long time. In 2011, it was indeed shown that oxidation of 5mC by TET (ten, eleven translocation) enzymes followed by TDG (thymine-DNA glycosylase)-mediated base excision of 5caC (5-carboxycytosine) constitutes a pathway for active DNA methylation. Dr. Zon further noted that additional independent work in 2011 showed that 5hmC (5-hydroxymethylcytosine) can be converted to 5hmU (5-hydroxymethyluracil), which can be a good substrate for TDG and may thus provide another mechanism for active cytosine demethylation in mammals. Dr. Zon pointed out that the oxidation-deamination mechanism in active cytosine demethylation was challenged in 2012 by Nabel et al. However, in 2013, Lie et al. cautioned that such deamination may occur in specific cellular contexts. Dr. Zon says that 5hmU in DNA is called “Base J.” It is present in all kinetoplastid flagellates studied—including Trypanosoma and Leishmania—but absent from other eukaryotes, prokaryotes, and viruses. Dr.