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Keywords = DNA–protein crosslink (DPC)

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19 pages, 606 KiB  
Review
Enzymatic Processing of DNA–Protein Crosslinks
by Maram M. Essawy and Colin Campbell
Genes 2024, 15(1), 85; https://doi.org/10.3390/genes15010085 - 10 Jan 2024
Cited by 6 | Viewed by 3285
Abstract
DNA–protein crosslinks (DPCs) represent a unique and complex form of DNA damage formed by covalent attachment of proteins to DNA. DPCs are formed through a variety of mechanisms and can significantly impede essential cellular processes such as transcription and replication. For this reason, [...] Read more.
DNA–protein crosslinks (DPCs) represent a unique and complex form of DNA damage formed by covalent attachment of proteins to DNA. DPCs are formed through a variety of mechanisms and can significantly impede essential cellular processes such as transcription and replication. For this reason, anti-cancer drugs that form DPCs have proven effective in cancer therapy. While cells rely on numerous different processes to remove DPCs, the molecular mechanisms responsible for orchestrating these processes remain obscure. Having this insight could potentially be harnessed therapeutically to improve clinical outcomes in the battle against cancer. In this review, we describe the ways cells enzymatically process DPCs. These processing events include direct reversal of the DPC via hydrolysis, nuclease digestion of the DNA backbone to delete the DPC and surrounding DNA, proteolytic processing of the crosslinked protein, as well as covalent modification of the DNA-crosslinked proteins with ubiquitin, SUMO, and Poly(ADP) Ribose (PAR). Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 1935 KiB  
Article
An Enzyme-Linked Immunosorbent Assay for the Detection of Mitochondrial DNA–Protein Cross-Links from Mammalian Cells
by Wenyan Xu and Linlin Zhao
DNA 2022, 2(4), 264-278; https://doi.org/10.3390/dna2040019 - 11 Nov 2022
Cited by 6 | Viewed by 3500
Abstract
DNA–Protein cross-links (DPCs) are cytotoxic DNA lesions with a protein covalently bound to the DNA. Although much has been learned about the formation, repair, and biological consequences of DPCs in the nucleus, little is known regarding mitochondrial DPCs. This is due in part [...] Read more.
DNA–Protein cross-links (DPCs) are cytotoxic DNA lesions with a protein covalently bound to the DNA. Although much has been learned about the formation, repair, and biological consequences of DPCs in the nucleus, little is known regarding mitochondrial DPCs. This is due in part to the lack of robust and specific methods to measure mitochondrial DPCs. Herein, we reported an enzyme-linked immunosorbent assay (ELISA)-based method for detecting mitochondrial DPCs formed between DNA and mitochondrial transcription factor A (TFAM) in cultured human cells. To optimize the purification and detection workflow, we prepared model TFAM-DPCs via Schiff base chemistry using recombinant human TFAM and a DNA substrate containing an abasic (AP) lesion. We optimized the isolation of TFAM-DPCs using commercial silica gel-based columns to achieve a high recovery yield for DPCs. We evaluated the microplate, DNA-coating solution, and HRP substrate for specific and sensitive detection of TFAM-DPCs. Additionally, we optimized the mtDNA isolation procedure to eliminate almost all nuclear DNA contaminants. For proof of concept, we detected the different levels of TFAM-DPCs in mtDNA from HEK293 cells under different biological conditions. The method is based on commercially available materials and can be amended to detect other types of DPCs in mitochondria. Full article
(This article belongs to the Special Issue From Mutation and Repair to Therapeutics)
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15 pages, 2795 KiB  
Article
Stalling of Eukaryotic Translesion DNA Polymerases at DNA-Protein Cross-Links
by Anna V. Yudkina, Evgeniy S. Shilkin, Alena V. Makarova and Dmitry O. Zharkov
Genes 2022, 13(2), 166; https://doi.org/10.3390/genes13020166 - 18 Jan 2022
Cited by 9 | Viewed by 2841
Abstract
DNA-protein cross-links (DPCs) are extremely bulky adducts that interfere with replication. In human cells, they are processed by SPRTN, a protease activated by DNA polymerases stuck at DPCs. We have recently proposed the mechanism of the interaction of DNA polymerases with DPCs, involving [...] Read more.
DNA-protein cross-links (DPCs) are extremely bulky adducts that interfere with replication. In human cells, they are processed by SPRTN, a protease activated by DNA polymerases stuck at DPCs. We have recently proposed the mechanism of the interaction of DNA polymerases with DPCs, involving a clash of protein surfaces followed by the distortion of the cross-linked protein. Here, we used a model DPC, located in the single-stranded template, the template strand of double-stranded DNA, or the displaced strand, to study the eukaryotic translesion DNA polymerases ζ (POLζ), ι (POLι) and η (POLη). POLι demonstrated poor synthesis on the DPC-containing substrates. POLζ and POLη paused at sites dictated by the footprints of the polymerase and the cross-linked protein. Beyond that, POLζ was able to elongate the primer to the cross-link site when a DPC was in the template. Surprisingly, POLη was not only able to reach the cross-link site but also incorporated 1–2 nucleotides past it, which makes POLη the most efficient DNA polymerase on DPC-containing substrates. However, a DPC in the displaced strand was an insurmountable obstacle for all polymerases, which stalled several nucleotides before the cross-link site. Overall, the behavior of translesion polymerases agrees with the model of protein clash and distortion described above. Full article
(This article belongs to the Special Issue Mechanisms of Replication of Damaged DNA)
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19 pages, 1807 KiB  
Review
DNA- and DNA-Protein-Crosslink Repair in Plants
by Janina Enderle, Annika Dorn and Holger Puchta
Int. J. Mol. Sci. 2019, 20(17), 4304; https://doi.org/10.3390/ijms20174304 - 3 Sep 2019
Cited by 18 | Viewed by 8207
Abstract
DNA-crosslinks are one of the most severe types of DNA lesions. Crosslinks (CLs) can be subdivided into DNA-intrastrand CLs, DNA-interstrand CLs (ICLs) and DNA-protein crosslinks (DPCs), and arise by various exogenous and endogenous sources. If left unrepaired before the cell enters S-phase, ICLs [...] Read more.
DNA-crosslinks are one of the most severe types of DNA lesions. Crosslinks (CLs) can be subdivided into DNA-intrastrand CLs, DNA-interstrand CLs (ICLs) and DNA-protein crosslinks (DPCs), and arise by various exogenous and endogenous sources. If left unrepaired before the cell enters S-phase, ICLs and DPCs pose a major threat to genomic integrity by blocking replication. In order to prevent the collapse of replication forks and impairment of cell division, complex repair pathways have emerged. In mammals, ICLs are repaired by the so-called Fanconi anemia (FA) pathway, which includes 22 different FANC genes, while in plants only a few of these genes are conserved. In this context, two pathways of ICL repair have been defined, each requiring the interaction of a helicase (FANCJB/RTEL1) and a nuclease (FAN1/MUS81). Moreover, homologous recombination (HR) as well as postreplicative repair factors are also involved. Although DPCs possess a comparable toxic potential to cells, it has only recently been shown that at least three parallel pathways for DPC repair exist in plants, defined by the protease WSS1A, the endonuclease MUS81 and tyrosyl-DNA phosphodiesterase 1 (TDP1). The importance of crosslink repair processes are highlighted by the fact that deficiencies in the respective pathways are associated with diverse hereditary disorders. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Plants)
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16 pages, 6337 KiB  
Article
Stimulation of Replication Template-Switching by DNA-Protein Crosslinks
by Laura T. Laranjo, Julie A. Klaric, Leah R. Pearlman and Susan T. Lovett
Genes 2019, 10(1), 14; https://doi.org/10.3390/genes10010014 - 27 Dec 2018
Cited by 7 | Viewed by 7296
Abstract
Covalent DNA protein crosslinks (DPCs) are common lesions that block replication. We examine here the consequence of DPCs on mutagenesis involving replicational template-switch reactions in Escherichia coli. 5-Azacytidine (5-azaC) is a potent mutagen for template-switching. This effect is dependent on DNA cytosine methylase [...] Read more.
Covalent DNA protein crosslinks (DPCs) are common lesions that block replication. We examine here the consequence of DPCs on mutagenesis involving replicational template-switch reactions in Escherichia coli. 5-Azacytidine (5-azaC) is a potent mutagen for template-switching. This effect is dependent on DNA cytosine methylase (Dcm), implicating the Dcm-DNA covalent complex trapped by 5-azaC as the initiator for mutagenesis. The leading strand of replication is more mutable than the lagging strand, which can be explained by blocks to the replicative helicase and/or fork regression. We find that template-switch mutagenesis induced by 5-azaC does not require double strand break repair via RecABCD; the ability to induce the SOS response is anti-mutagenic. Mutants in recB, but not recA, exhibit high constitutive rates of template-switching, and we suggest that RecBCD-mediated DNA degradation prevents template-switching associated with fork regression. A mutation in the DnaB fork helicase also promotes high levels of template-switching. We also find that other DPC-inducers, formaldehyde (a non-specific crosslinker) and ciprofloxacin (a topoisomerase II poison) are also strong mutagens for template-switching with similar genetic properties. Induction of mutations and genetic rearrangements that occur by template-switching may constitute a previously unrecognized component of the genotoxicity and genetic instability promoted by DPCs. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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