Epigenetic shielding: 5-hydroxymethylcytosine and 5-carboxylcytosine modulate UV induction of DNA photoproducts
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CitationLiu, Jue Judy. 2014. Epigenetic shielding: 5-hydroxymethylcytosine and 5-carboxylcytosine modulate UV induction of DNA photoproducts. Doctoral dissertation, Harvard University.
AbstractMaintaining the balance between dynamic DNA methylation and demethylation is crucial to mammalian development and pathogenesis. In vitro methylation at the C-5 position of cytosine enhances cyclobutane pyrimidine dimer (CPD) formation and promotes transition mutations. While the loss of 5-hydroxymethylcytosine (5hmC) and inactivation of the ten-eleven translocation (TET) family have been implicated in cancers, and repeated exposure to UV radiation is a known risk factor for developing skin cancers, the link between DNA demethylation and UV damage has not yet been illustrated. We report that hydroxylation and carboxylation of 5-methylcytosine mitigate methylation-induced CPD enhancement upon UV irradiation. However, 5hmC also increases UV induction of (6-4) photoproducts. In a melanoma cell model, this duality by 5hmC in modulating the UV response is accentuated through TET2 overexpression. These findings implicate the DNA demethylation intermediates 5-hydroxymethylcytosine (5hmC) and 5-carboxylcytosine (5caC) as selective epigenetic shields against UV induction of DNA photoproducts.
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