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

被引:58
|
作者
Szulik, Marta W. [1 ,2 ]
Pallan, Pradeep S. [3 ,4 ]
Nocek, Boguslaw [5 ]
Voehler, Markus [1 ,2 ]
Banerjee, Surajit [6 ,7 ]
Brooks, Sonja [2 ,8 ]
Joachimiak, Andrzej [5 ]
Egli, Martin [3 ,4 ]
Eichman, Brandt F. [2 ,8 ]
Stone, Michael P. [1 ,2 ]
机构
[1] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Vanderbilt Inst Chem Biol, Dept Chem, Nashville, TN 37235 USA
[2] Vanderbilt Univ, Struct Biol Ctr, Nashville, TN 37235 USA
[3] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Vanderbilt Inst Chem Biol, Dept Biochem,Sch Med, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Sch Med, Struct Biol Ctr, Nashville, TN 37232 USA
[5] Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA
[6] Cornell Univ, Argonne Natl Lab, Northeastern Collaborat Access Team, Argonne, IL 60439 USA
[7] Cornell Univ, Argonne Natl Lab, Dept Chem & Chem Biol, Argonne, IL 60439 USA
[8] Vanderbilt Univ, Dept Biol Sci, Vanderbilt Inst Chem Biol, Nashville, TN 37235 USA
关键词
THYMINE DNA GLYCOSYLASE; B-DNA; STRUCTURAL ENERGETICS; MAMMALIAN DNA; PROTON RESONANCES; CRYSTAL-STRUCTURE; NMR-SPECTROSCOPY; EXCISION-REPAIR; NUCLEIC-ACIDS; ADENINE TRACT;
D O I
10.1021/bi501534x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
5-Hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) form during active demethylation of 5-methylcytosine (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'-T(8)X(9)G(10)-3' sequence of the DDD, were compared. The presence of 5caC at the X(9) 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(5):T(8), whereas 5caC did not. At the oxidized base pair G(4):X(9), 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(3):G(10). No evidence was observed for imino tautomerization, accompanied by wobble base pairing, for 5hmC, 5fC, or 5caC when positioned at base pair G(4):X(9); 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(4) 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.
引用
收藏
页码:1294 / 1305
页数:12
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