DNA polymerase structure-based insight on the mutagenic properties of 8-oxoguanine

Beard, William A.; Batra, V.K.; Wilson, Samuel H.

doi:10.1016/j.mrgentox.2010.07.013

Cited by 84 publications

(99 citation statements)

References 38 publications

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“…To this end, we determined binary (pol/DNA) and ternary (pol/DNA/dNTP) X-ray crystal structures of human DNA polymerase β (pol β) with 5ClC in the templating position of a 1-nt-gapped DNA duplex (Table 2). Pol β is a model mammalian DNA polymerase involved in base excision repair and may encounter DNA lesions in the templating strand during repair of the genome (32)(33)(34). The binary DNA complex structure with 5ClC in the templating position diffracted to 2.0 Å.…”

Section: Results 5clc Is a Mutagenic Base That Is Easily Bypassed By mentioning

confidence: 99%

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Fedeles

Freudenthal

Yau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation.5-chloro-deoxycytidine | hypochlorite | myeloperoxidase | inflammatory bowel disease | carcinogenesis

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Section: Results 5clc Is a Mutagenic Base That Is Easily Bypassed By mentioning

confidence: 99%

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Fedeles

Freudenthal

Yau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been demonstrated that active site flexibility around the template base allows conformational alternation of 8-oxo-G in DNA polymerases with standard active site dimensions (25). This template flexibility allows the syn 8-oxo-G base to form a potent base pair with mismatched anti dATP, causing A misincorporations by virtually all classes of DNA polymerases (2,4,26) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Unique active site promotes error-free replication opposite an 8-oxo-guanine lesion by human DNA polymerase iota

Kirouac

2011

Proc. Natl. Acad. Sci. U.S.A.

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The 8-oxo-guanine (8-oxo-G) lesion is the most abundant and mutagenic oxidative DNA damage existing in the genome. Due to its dual coding nature, 8-oxo-G causes most DNA polymerases to misincorporate adenine. Human Y-family DNA polymerase iota (polι) preferentially incorporates the correct cytosine nucleotide opposite 8-oxo-G. This unique specificity may contribute to polι's biological role in cellular protection against oxidative stress. However, the structural basis of this preferential cytosine incorporation is currently unknown. Here we present four crystal structures of polι in complex with DNA containing an 8-oxo-G lesion, paired with correct dCTP or incorrect dATP, dGTP, and dTTP nucleotides. An exceptionally narrow polι active site restricts the purine bases in a syn conformation, which prevents the dual coding properties of 8-oxo-G by inhibiting syn/anti conformational equilibrium. More importantly, the 8-oxo-G base in a syn conformation is not mutagenic in polι because its Hoogsteen edge does not form a stable base pair with dATP in the narrow active site. Instead, the syn 8-oxo-G template base forms the most stable replicating base pair with correct dCTP due to its small pyrimidine base size and enhanced hydrogen bonding with the Hoogsteen edge of 8-oxo-G. In combination with site directed mutagenesis, we show that Gln59 in the finger domain specifically interacts with the additional O 8 atom of the lesion base, which influences nucleotide selection, enzymatic efficiency, and replication stalling at the lesion site. Our work provides the structural mechanism of high-fidelity 8-oxo-G replication by a human DNA polymerase.DNA replication | Y family polymerase | translesion DNA synthesis | oxidative lesion | DNA mutagenesis

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“…The slight preference of POL ␤ for rCTP over rATP insertion opposite 8-oxodG mirrors a similar small discrimination between dCTP and dATP (27). The major determinant of dual coding by a template 8-oxodG is its ability to assume both syn and anti conformations (27)(28)(29). Our data indicate that this property is not detectably affected by the presence of a C2Ј oxygen and ribonucleotide insertion opposite a template 8-oxodG appears to follow the same rules as deoxyribonucleotide incorporation.…”

Section: Discussionmentioning

confidence: 99%

Formation and Repair of Mismatches Containing Ribonucleotides and Oxidized Bases at Repeated DNA Sequences

Cilli

Minoprio

Bossa

et al. 2015

Journal of Biological Chemistry

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Background: Whether ribonucleotide and base excision repair (RER and BER) interfere during repair synthesis events is unknown. Results: Complex mispairs containing ribonucleotides and oxidized bases are formed by polymerase ␤ and processed by RER and BER enzymes. Conclusion: Complex lesions modify the efficiency of DNA/RNA repair systems. Significance: This work explains how complex mispairs can compromise BER and RER.

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DNA polymerase structure-based insight on the mutagenic properties of 8-oxoguanine

Cited by 84 publications

References 38 publications

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Unique active site promotes error-free replication opposite an 8-oxo-guanine lesion by human DNA polymerase iota

Formation and Repair of Mismatches Containing Ribonucleotides and Oxidized Bases at Repeated DNA Sequences

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