Specificity and Catalytic Mechanism in Family 5 Uracil DNA Glycosylase

Xia, Bo; Liu, Yinling; Li, Wei; Brice, Allyn R.; Dominy, Brian N.; Cao, Weiguo

doi:10.1074/jbc.m114.567354

Cited by 23 publications

(26 citation statements)

References 63 publications

(80 reference statements)

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“…Whereas the highest measured mutagenic potential for 8-oxo-dG is 10% [136]. [84]. However, the same mutational profile can 293 also occur due to replication errors.…”

mentioning

confidence: 99%

Mitochondrial DNA: Radically free of free-radical driven mutations

Kauppila

Stewart

2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered the accumulation of mitochondrial DNA mutations in association with a mosaic pattern of cells displaying mitochondrial dysfunction in ageing individuals. Unfortunately, the underlying mechanisms are far less straightforward than originally anticipated. Recent research on mitochondria reveals that these genomes are far less helpless than originally envisioned. Additionally, new technologies have allowed us to analyze the mutational signatures of many more somatic mitochondrial DNA mutations, revealing surprising patterns that are inconsistent with a DNA-oxidative damage based hypothesis. In this review, we will discuss these recent observations and new insights into the eccentricities of mitochondrial genetics, and their impact on our understanding of mitochondrial mutations and their role in the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.

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“…Whereas the highest measured mutagenic potential for 8-oxo-dG is 10% [136]. [84]. However, the same mutational profile can 293 also occur due to replication errors.…”

mentioning

confidence: 99%

Mitochondrial DNA: Radically free of free-radical driven mutations

Kauppila

Stewart

2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…5A–B). The first histidine residue in motif 2 is proposed to form a hydrogen bond with O2 of uracil to stabilize the negatively charged uracil leaving group in family 1 UNG, family 4 UDGa and family 5 UDGb [21, 34, 48]. It is likely that H210 plays a similar catalytic role in Lin SMUG1-like glycosylase (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As for the UDG activity, family 1 and 4 enzymes can all remove uracil from double- and single-stranded DNA [34]. Some families 2 and 5 enzymes prefer double-stranded DNA [13, 21]. Family 3 SMUG1 enzymes were first identified as a single-stranded selective UDG [18], yet later UDG activity on double-stranded DNA was detected [19, 23, 25, 47, 50].…”

Section: Resultsmentioning

confidence: 99%

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Identification of a prototypical single-stranded uracil DNA glycosylase from Listeria innocua

Yang

Guevara

et al. 2017

DNA Repair

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A recent phylogenetic study on UDG superfamily estimated a new clade of family 3 enzymes (SMUG1-like), which shares a lower homology with canonic SMUG1 enzymes. The enzymatic properties of the newly found putative DNA glycosylase are unknown. To test the potential UDG activity and evaluate phylogenetic classification, we isolated one SMUG1-like glycosylase representative from Listeria innocua (Lin). A biochemical screening of DNA glycosylase activity in vitro indicates that Lin SMUG1-like glycosylase is a single-strand selective uracil DNA glycosylase. The UDG activity on DNA bubble structures provides clue to its physiological significance in vivo. Mutagenesis and molecular modeling analyses reveal that Lin SMUG1-like glycosylase has similar functional motifs with SMUG1 enzymes; however, it contains a distinct catalytic doublet S67-S68 in motif 1 that is not found in any families in the UDG superfamily. Experimental investigation shows that the S67M-S68N double mutant is catalytically more active than either S67M or S68N single mutant. Coupled with mutual information analysis, the results indicate a high degree of correlation in the evolution of SMUG1-like enzymes. This study underscores the functional and catalytic diversity in the evolution of enzymes in UDG superfamily.

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“…Family 4 UDGa, found in prokaryotic organisms, is a UDG but the full spectrum of its activity against all deaminated bases is not known ( 15 ). Family 5 UDGb, also found in prokaryotic organisms, is not only a UDG but also a hypoxanthine and a xanthine DNA glycosylase ( 16 ). However, the UDG activity from family 5 UDGb is limited to double-stranded uracil-containing DNA and the activity on A/U base pairs is lower than that on mismatched base pairs ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

A structural determinant in the uracil DNA glycosylase superfamily for the removal of uracil from adenine/uracil base pairs

Lee

Liu

Lee

et al. 2014

Nucleic Acids Research

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The uracil DNA glycosylase superfamily consists of several distinct families. Family 2 mismatch-specific uracil DNA glycosylase (MUG) from Escherichia coli is known to exhibit glycosylase activity on three mismatched base pairs, T/U, G/U and C/U. Family 1 uracil N-glycosylase (UNG) from E. coli is an extremely efficient enzyme that can remove uracil from any uracil-containing base pairs including the A/U base pair. Here, we report the identification of an important structural determinant that underlies the functional difference between MUG and UNG. Substitution of a Lys residue at position 68 with Asn in MUG not only accelerates the removal of uracil from mismatched base pairs but also enables the enzyme to gain catalytic activity on A/U base pairs. Binding and kinetic analysis demonstrate that the MUG-K68N substitution results in enhanced ground state binding and transition state interactions. Molecular modeling reveals that MUG-K68N, UNG-N123 and family 5 Thermus thermophiles UDGb-A111N can form bidentate hydrogen bonds with the N3 and O4 moieties of the uracil base. Genetic analysis indicates the gain of function for A/U base pairs allows the MUG-K68N mutant to remove uracil incorporated into the genome during DNA replication. The implications of this study in the origin of life are discussed.

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Specificity and Catalytic Mechanism in Family 5 Uracil DNA Glycosylase

Cited by 23 publications

References 63 publications

Mitochondrial DNA: Radically free of free-radical driven mutations

Mitochondrial DNA: Radically free of free-radical driven mutations

Identification of a prototypical single-stranded uracil DNA glycosylase from Listeria innocua

A structural determinant in the uracil DNA glycosylase superfamily for the removal of uracil from adenine/uracil base pairs

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