Effects of Tet-Induced Oxidation Products of 5-Methylcytosine on DNA Replication in Mammalian Cells

Ji, Debin; You, Changjun; Wang, Pengcheng; Wang, Yinsheng

doi:10.1021/tx500169u

Cited by 13 publications

(23 citation statements)

References 37 publications

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“…In addition, 5-hmC did not compromise appreciably the efficiency or accuracy of transcription in vitro or in HEK293T cells. 242 The lack of pronounced deleterious effects of 5-hmC, 5-fC, and 5-caC on replication or transcription is in keeping with the potential roles of these oxidized 5-mC derivatives in epigenetic regulation.…”

Section: Repair and Biological Consequences Of Oxidative Stress-inmentioning

confidence: 59%

“…243 Additionally, the substrate specificity was reduced by ∼30-fold for the 5-fC-containing template in comparison with the C template. 243 Later, You et al 242 revealed that 5-fC and 5-caC displayed marginal mutagenic (∼0.7–1.7%) and modest inhibitory (31–50%) effects on transcription mediated by T7RNAP or human RNA polymerase II (hRNAPII) in vitro and in HEK293T cells. In addition, 5-hmC did not compromise appreciably the efficiency or accuracy of transcription in vitro or in HEK293T cells.…”

Section: Repair and Biological Consequences Of Oxidative Stress-inmentioning

confidence: 99%

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Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Cui

Niedernhofer

et al. 2016

Chem. Res. Toxicol.

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138

132

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A variety of endogenous and exogenous agents can induce DNA damage and lead to genomic instability. Reactive oxygen species (ROS), an important class of DNA damaging agents, are constantly generated in cells as a consequence of endogenous metabolism, infection/inflammation, and/or exposure to environmental toxicants. A wide array of DNA lesions can be induced by ROS directly, including single-nucleobase lesions, tandem lesions, and hypochlorous acid (HOCl)/hypobromous acid (HOBr)-derived DNA adducts. ROS can also lead to lipid peroxidation, whose byproducts can also react with DNA to produce exocyclic DNA lesions. A combination of bioanalytical chemistry, synthetic organic chemistry, and molecular biology approaches have provided significant insights into the occurrence, repair, and biological consequences of oxidatively induced DNA lesions. The involvement of these lesions in the etiology of human diseases and aging was also investigated in the past several decades, suggesting that the oxidatively induced DNA adducts, especially bulky DNA lesions, may serve as biomarkers for exploring the role of oxidative stress in human diseases. The continuing development and improvement of LC-MS/MS coupled with the stable isotope-dilution method for DNA adduct quantification will further promote research about the clinical implications and diagnostic applications of oxidatively induced DNA adducts.

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Section: Repair and Biological Consequences Of Oxidative Stress-inmentioning

confidence: 59%

Section: Repair and Biological Consequences Of Oxidative Stress-inmentioning

confidence: 99%

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Cui

Niedernhofer

et al. 2016

Chem. Res. Toxicol.

Self Cite

138

132

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“…10,15,27,28 One challenging step in this experimental system is the construction of double-stranded vectors containing site-specifically inserted DNA lesions. However, the use of gapped vector-based strategy enables the facile preparation of site-specifically modified plasmids.…”

Section: Ms-based Assays For Replication Studies In Mammalian Cellsmentioning

confidence: 99%

“…8-29 Furthermore, we have employed these methods to define the respective roles of various translesion synthesis (TLS) DNA polymerases and DNA repair proteins in the replicative and transcriptional alterations induced by DNA lesions. 8-27,29 …”

Section: Introductionmentioning

confidence: 99%

Mass Spectrometry-Based Quantitative Strategies for Assessing the Biological Consequences and Repair of DNA Adducts

You

Wang

2016

Acc. Chem. Res.

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The genetic integrity of living organisms is constantly threatened by environmental and endogenous sources of DNA damaging agents that can induce a plethora of chemically modified DNA lesions. Unrepaired DNA lesions may elicit cytotoxic and mutagenic effects and contribute to the development of human diseases including cancer and neurodegeneration. Understanding the deleterious outcomes of DNA damage necessitates the investigation about the effects of DNA adducts on the efficiency and fidelity of DNA replication and transcription. Conventional methods for measuring lesion-induced replicative or transcriptional alterations often require time-consuming colony screening and DNA sequencing procedures. Recently, a series of mass spectrometry (MS)-based strategies have been developed in our laboratory as an efficient platform for qualitative and quantitative analyses of the changes in genetic information induced by DNA adducts during DNA replication and transcription. During the past few years, our laboratory has used these MS-based methods for assessing the replicative or transcriptional blocking and miscoding properties of more than 30 distinct DNA adducts. When combined with genetic manipulation, these methods have also been successfully employed for revealing the roles of various DNA repair proteins or translesion synthesis DNA polymerases in modulating the adverse effects of DNA lesions on transcription or replication in mammalian and bacterial cells. In this Account, we focus on the development of MS-based approaches for determining the effects of DNA adducts on DNA replication and transcription in vitro as well as in bacterial and mammalian cells. We also highlight their applications to lesion bypass, mutagenesis and repair studies of three representative types of DNA lesions, i.e., methylglyoxal-induced N2-(1-carboxyethyl)-2'-deoxyguanosine (N2-CEdG), oxidatively induced 8,5'-cyclopurine-2'-deoxynucleosides, and regioisomeric alkylated thymidine lesions. Specially, we discuss the similar and distinct effects of the minor-groove DNA lesions including N2-CEdG and O2-alkylated thymidine lesions as well as the major-groove O4-alkylated thymidine lesions on DNA replication and transcription machinery. The MS-based strategies described herein should be generally applicable for quantitative measurement of the biological consequences and repair of other DNA lesions in vitro and in cells.

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“…In addition to this and other potential AM‐AR pathways, hemi‐modified CpG containing oxidized mC derivatives have been shown to reduce the efficiency of DNMT1‐catalyzed maintenance methylation compared to hemi‐methylated CpG. Consequently, hmC, fC, and caC promote replication‐dependent passive dilution of mC via active modification (AM‐PD, Scheme ) . For recent reviews discussing these pathways, see Refs,,.…”

Section: Introductionmentioning

confidence: 99%

Recognition of Oxidized 5‐Methylcytosine Derivatives in DNA by Natural and Engineered Protein Scaffolds

Muñoz‐López

Summerer

2017

The Chemical Record

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Methylation of genomic cytosine to 5-methylcytosine is a central regulatory element of mammalian gene expression with important roles in development and disease. 5-methylcytosine can be actively reversed to cytosine via oxidation to 5-hydroxymethyl-, 5-formyl-, and 5-carboxylcytosine by ten-eleven-translocation dioxygenases and subsequent base excision repair or replication-dependent dilution. Moreover, the oxidized 5-methylcytosine derivatives are potential epigenetic marks with unique biological roles. Key to a better understanding of these roles are insights into the interactions of the nucleobases with DNA-binding protein scaffolds: Natural scaffolds involved in transcription, 5-methylcytosine-reading and -editing as well as general chromatin organization can be selectively recruited or repulsed by oxidized 5-methylcytosines, forming the basis of their biological functions. Moreover, designer protein scaffolds engineered for the selective recognition of oxidized 5-methylcytosines are valuable tools to analyze their genomic levels and distribution. Here, we review recent structural and functional insights into the molecular recognition of oxidized 5-methylcytosine derivatives in DNA by selected protein scaffolds.

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Effects of Tet-Induced Oxidation Products of 5-Methylcytosine on DNA Replication in Mammalian Cells

Cited by 13 publications

References 37 publications

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage

Mass Spectrometry-Based Quantitative Strategies for Assessing the Biological Consequences and Repair of DNA Adducts

Recognition of Oxidized 5‐Methylcytosine Derivatives in DNA by Natural and Engineered Protein Scaffolds

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