5-Pyrimidinecarboxaldehyde, 4-amino-1,2-dihydro-2-oxo-

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CAS: 4425-59-6
MF: C5H5N3O2
MW: 139.1121
Synonyms: 5-Pyrimidinecarboxaldehyde, 4-amino-1,2-dihydro-2-oxo-

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Xiang Zhou

Wuhan University
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Tian Tian

Wuhan University
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Shaoru Wang

Wuhan University
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XiangShi Tan

Fudan University
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Pengyuan Yang

Fudan University
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Tong-Chuan He

The University of Chicago Medical Center
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Henry S. White

University of Utah
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Peter K. Davies

University of Pennsylvania
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Michael P. Stone

University of Connecticut
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Co-reporter: Marta W. Szulik, Pradeep S. Pallan, Boguslaw Nocek, Markus Voehler, Surajit Banerjee, Sonja Brooks, Andrzej Joachimiak, Martin Egli, Brandt F. Eichman, and Michael P. Stone
pp: 1294-1305
Publication Date(Web):January 29, 2015
DOI: 10.1021/bi501534x
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′-T8X9G10-3′ sequence of the DDD, were compared. The presence of 5caC at the X9 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 A5:T8, whereas 5caC did not. At the oxidized base pair G4:X9, 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 C3:G10. No evidence was observed for imino tautomerization, accompanied by wobble base pairing, for 5hmC, 5fC, or 5caC when positioned at base pair G4:X9; 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 N4 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.

Frank M. Raushel

Texas A&M University niversity
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