Mass Spectrometry‐Based Tools to Characterize <scp>DNA</scp>–Protein Cross‐Linking by <i>Bis</i>‐Electrophiles

Groehler, Arnold S.; Degner, Amanda; Tretyakova, Natalia

doi:10.1111/bcpt.12751

Cited by 23 publications

(20 citation statements)

References 112 publications

(156 reference statements)

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“…Although chemotherapeutics, such as cisplatin derivatives and nitrogen mustards, are mainly known to form DNA adducts and DNA ICLs, they can also form DPCs [ 16 ]. Cisplatin can induce DPCs by attacking the N7 atom of purine bases, which can then be connected to cysteine, arginine, and lysine side chains by a subsequent nucleophilic attack on the platinum center ( Fig.…”

Section: Dna-protein Crosslinks: a Diverse Class Of Lesionsmentioning

confidence: 99%

How to fix DNA-protein crosslinks

Kühbacher

Duxin

2020

DNA Repair

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Proteins that act on DNA, or are in close proximity to it, can become inadvertently crosslinked to DNA and form highly toxic lesions, known as DNA-protein crosslinks (DPCs). DPCs are generated by different chemotherapeutics, environmental or endogenous sources of crosslinking agents, or by lesions on DNA that stall the catalytic cycle of certain DNA processing enzymes. These bulky adducts impair processes on DNA such as DNA replication or transcription, and therefore pose a serious threat to genome integrity. The large diversity of DPCs suggests that there is more than one canonical mechanism to repair them. Indeed, many different enzymes have been shown to act on DPCs by either processing the protein, the DNA or the crosslink itself. In addition, the cell cycle stage or cell type are likely to dictate pathway choice. In recent years, a detailed understanding of DPC repair during S phase has started to emerge. Here, we review the current knowledge on the mechanisms of replication-coupled DPC repair, and describe and also speculate on possible pathways that remove DPCs outside of S phase. Moreover, we highlight a recent paradigm shifting finding that indicates that DPCs are not always detrimental, but can also play a protective role, preserving the genome from more deleterious forms of DNA damage.

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Section: Dna-protein Crosslinks: a Diverse Class Of Lesionsmentioning

confidence: 99%

How to fix DNA-protein crosslinks

Kühbacher

Duxin

2020

DNA Repair

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“…Because of the presence of two epoxy moieties in the molecule, DEB not only has stronger reactivity in comparison with EB and EBD [ 89 – 91 ], but also can form DNA cross-links [ 7 , 83 , 92 – 96 ] and DNA-protein cross-links [ 97 ]. As a result, clastogenicity of DEB is very high; among ~100 IARC carcinogens (Group 1, 2A, and 2B), DEB shows highest level of micronucleus (MN) induction in mice [ 98 ].…”

Section: Introductionmentioning

confidence: 99%

1,3-Butadiene: a ubiquitous environmental mutagen and its associations with diseases

Chen

Zhang

2022

Genes and Environ

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Abstract1,3-Butadiene (BD) is a petrochemical manufactured in high volumes. It is a human carcinogen and can induce lymphohematopoietic cancers, particularly leukemia, in occupationally-exposed workers. BD is an air pollutant with the major environmental sources being automobile exhaust and tobacco smoke. It is one of the major constituents and is considered the most carcinogenic compound in cigarette smoke. The BD concentrations in urban areas usually vary between 0.01 and 3.3 μg/m3 but can be significantly higher in some microenvironments. For BD exposure of the general population, microenvironments, particularly indoor microenvironments, are the primary determinant and environmental tobacco smoke is the main contributor. BD has high cancer risk and has been ranked the second or the third in the environmental pollutants monitored in most urban areas, with the cancer risks exceeding 10-5. Mutagenicity/carcinogenicity of BD is mediated by its genotoxic metabolites but the specific metabolite(s) responsible for the effects in humans have not been determined. BD can be bioactivated to yield three mutagenic epoxide metabolites by cytochrome P450 enzymes, or potentially be biotransformed into a mutagenic chlorohydrin by myeloperoxidase, a peroxidase almost specifically present in neutrophils and monocytes. Several urinary BD biomarkers have been developed, among which N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine is the most sensitive and is suitable for biomonitoring BD exposure in the general population. Exposure to BD has been associated with leukemia, cardiovascular disease, and possibly reproductive effects, and may be associated with several cancers, autism, and asthma in children. Collectively, BD is a ubiquitous pollutant that has been associated with a range of adverse health effects and diseases with children being a subpopulation with potentially greater susceptibility. Its adverse effects on human health may have been underestimated and more studies are needed.

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“…Unlike other types of DNA damage, DPCs are massively diverse 1 2 . Studies have demonstrated that hundreds of cellular proteins can become crosslinked to DNA and that for each protein there are, in principle, numerous amino acid side chains that could become covalently attached to cellular DNA 3 . In addition, there are numerous chemical attachment points for proteins onto the DNA backbone, including several positions on the nucleotide bases as well as on the ribose sugar 4 5 .…”

Section: Introductionmentioning

confidence: 99%

A Simple, Rapid, and Quantitative Assay to Measure Repair of DNA-protein Crosslinks on Plasmids Transfected into Mammalian Cells

Chesner

Campbell

2018

JoVE

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The purpose of this method is to provide a flexible, rapid, and quantitative technique to examine the kinetics of DNA-protein crosslink (DPC) repair in mammalian cell lines. Rather than globally assaying removal of xenobiotic-induced or spontaneous chromosomal DPC removal, this assay examines the repair of a homogeneous, chemically defined lesion specifically introduced at one site within a plasmid DNA substrate. Importantly, this approach avoids the use of radioactive materials and is not dependent on expensive or highly-specialized technology. Instead, it relies on standard recombinant DNA procedures and widely available quantitative real time PCR instrumentation. Given the inherent flexibility of the strategy utilized, the size of the crosslinked protein, as well as the nature of the chemical linkage and the precise DNA sequence context of the attachment site can be varied to address the respective contributions of these parameters to the overall efficiency of DPC repair. Using this method, plasmids containing a site-specific DPC were transfected into cells and low molecular weight DNA recovered at various times post-transfection. Recovered DNA is then subjected to strand-specific primer extension using a primer complementary to the damaged strand of the plasmid. Since the DPC lesion blocks Taq DNA polymerase, the ratio of repaired to un-repaired DNA can be quantitatively assessed using qPCR. Cycle threshold values are used to calculate percent repair at various time points in the respective cell lines. This strand-specific primer extension-qPCR method can also be used to quantitatively assess the repair kinetics of any DNA adduct that blocks Taq polymerase.

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Mass Spectrometry‐Based Tools to Characterize DNA–Protein Cross‐Linking by Bis‐Electrophiles

Cited by 23 publications

References 112 publications

How to fix DNA-protein crosslinks

How to fix DNA-protein crosslinks

1,3-Butadiene: a ubiquitous environmental mutagen and its associations with diseases

A Simple, Rapid, and Quantitative Assay to Measure Repair of DNA-protein Crosslinks on Plasmids Transfected into Mammalian Cells

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