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5-Hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) form during active demethylation of 5methylcytosine (5mC) and are implicated in epigenetic regulation of the genome. They are differentially processed by thymine DNA glycosylase (TDG), an enzyme involved in active demethylation of 5mC. Three modified Dickerson−Drew dodecamer (DDD) sequences, amenable to crystallographic and spectroscopic analyses and containing the 5′-CG-3′ sequence associated with genomic cytosine methylation, containing 5hmC, 5fC, or 5caC placed site-specifically into the 5′-TXG-3′ sequence of the DDD, were compared. The presence of 5caC at the X base increased the stability of the DDD, whereas 5hmC or 5fC did not. Both 5hmC and 5fC increased imino proton exchange rates and calculated rate constants for base pair opening at the neighboring base pair A:T, whereas 5caC did not. At the oxidized base pair G:X, 5fC exhibited an increase in the imino proton exchange rate and the calculated kop. In all cases, minimal effects to imino proton exchange rates occurred at the neighboring base pair C:G. No evidence was observed for imino tautomerization, accompanied by wobble base pairing, for 5hmC, 5fC, or 5caC when positioned at base pair G:X; each favored Watson−Crick base pairing. However, both 5fC and 5caC exhibited intranucleobase hydrogen bonding between their formyl or carboxyl oxygens, respectively, and the adjacent cytosine N exocyclic amines. The lesion-specific differences observed in the DDD may be implicated in recognition of 5hmC, 5fC, or 5caC in DNA by TDG. However, they do not correlate with differential excision of 5hmC, 5fC, or 5caC by TDG, which may be mediated by differences in transition states of the enzyme-bound complexes. C methylation by DNA methyltransferases to form 5-methylcytosine (5mC) is important in epigenetic regulation of the eukaryotic genome. The reconversion of 5mC to cytosine during active demethylation involves the stepwise oxidation of 5mC. Oxidation of 5mC to 5hydroxymethylcytosine (5hmC) is accomplished by ten-eleven translocation (TET) dioxygenases and occurs in response to oxidative stress as a consequence of UV radiation. Further oxidation of 5hmC by TET dioxygenases forms 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). These have been detected in cellular DNA. Both 5fC and 5caC, but not 5hmC, are substrates for thymine DNA glycosylase (TDG), consistent with the greater abundance of 5hmC in mammalian tissues and implicating catalyzed base excision of oxidized 5mC derivatives in active demethylation. The differential processing of 5fC and 5caC vs 5hmC by TDG could be mediated by their differential recognition in DNA. Recently, Raiber et al. reported that a DNA dodecamer containing three 5fC sites in an iterated CG repeat sequence exhibited 5fC-specific helical unwinding, due to specific changes in the geometry of the grooves and base pairs involving 5fC. Received: December 17, 2014 Published: January 29, 2015 Article pubs.acs.org/biochemistry © 2015 American Chemical Society 1294 DOI: 10.1021/bi501534x Biochemistry 2015, 54, 1294−1305 This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

biochemistry

Correction to Differential Stabilities and Sequence-Dependent Base Pair Opening Dynamics of Watson–Crick Base Pairs with 5-Hydroxymethylcytosine, 5-Formylcytosine, or 5-Carboxylcytosine