Solution structure of a nitrous acid induced DNA interstrand cross-link

Edfeldt, N. B. Fredrik; Harwood, Eric A.; Sigurdsson, Snorri Th.; Hopkins, Paul B.; Reid, Brian R.

doi:10.1093/nar/gkh606

Cited by 33 publications

(35 citation statements)

References 41 publications

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“…These lesions are formed endogenously through byproducts of lipid peroxidation, such as malondialdehyde (7, 11–12) and many other endogenous sources (8–10, 39). Cytotoxic ICLs are also formed by many common chemotherapeutic bifunctional agents, such as cisplatin, mitomycin C, nitrosoureas, and nitrogen mustards (1, 3, 40).…”

Section: Discussionmentioning

confidence: 99%

Cross-Link Structure Affects Replication-Independent DNA Interstrand Cross-Link Repair in Mammalian Cells

et al. 2010

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DNA interstrand cross-links (ICLs) are cytotoxic products of common anti-cancer drugs and cellular metabolic processes, whose mechanism(s) of repair remain poorly understood. In this study, we show that cross-link structure affects ICL repair in non-replicating reporter plasmids that contain a mispaired N 4 C-ethyl-N 4 C (C-C), N3T-ethyl-N3T (T-T), or N1I-ethyl-N3T (I-T) ICL. The T-T and I-T cross-links obstruct the hydrogen bond face of the base and mimic the N1G-ethyl-N3C ICL created by bis-chloroethylnitrosourea, whereas the C-C cross-link does not interfere with base pair formation. Host-cell reactivation (HCR) assays in human and hamster cells showed that repair of these ICLs primarily involves the transcription-coupled nucleotide excision repair (TC-NER) pathway. Repair of the C-C ICL was five-fold more efficient than repair of the T-T or I-T ICLs, suggesting the latter's cross-links hinder lesion bypass following initial ICL unhooking. Luciferase expression from plasmids containing a C-C crosslink remnant on either the transcribed or nontranscribed strand increased in NER-deficient cells, indicating NER involvement occurs at a step prior to remnant removal, whereas expression from similar T-T remnant plasmids was inhibited in NER-deficient cells, demonstrating NER is required for remnant removal. Sequence analysis on repaired plasmids showed a high proportion of Cs inserted at the site of the T-T and I-T cross-links and HCR assays showed that Rev1 was likely responsible for these insertions. In contrast, both Cs and Gs were inserted at the C-C cross-link site and Rev1 was not required for repair, suggesting replicative or other translesion polymerases can bypass the C-C remnant.Interstrand cross-links (ICLs) covalently link two bases on opposite strands of the DNA helix and can be formed by both endogenous and exogenous sources. ICLs are among the most cytotoxic DNA lesions to cells because they prevent the two DNA strands from separating, thereby inhibiting DNA replication and transcription. Additionally, DNA ICLs are cytotoxic products of bifunctional alkylating agents commonly used in cancer chemotherapy (1-3). If left unrepaired, ICLs signal cell death pathways. However, some cancer patients can become † This research was supported by grants from the National Cancer Institute (CA082785, CA016783, and T32CA09110), the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canada Research Chair program, and the American Heart Association (103527). *Correspondence should be addressed to Paul S. Miller, pmiller@jhsph.edu, Phone: (410)-955-3489, Fax: (410)-955-2926. Supporting Information Available: Figure S1 shows the sequences of non-damaged, cross-linked, and cross-link remnant containing duplexes used to construct the reporter plasmids. Figure S2 illustrates the structure of a N 4 C-ethyl-N 4 C interstrand cross-link placed in a -CG-sequence and characterization of a -CG-cross-linked plasmid. Figure S3 displays repair efficiencies of ICLs transfected into wild type and XRCC3-d...

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Section: Discussionmentioning

confidence: 99%

Cross-Link Structure Affects Replication-Independent DNA Interstrand Cross-Link Repair in Mammalian Cells

et al. 2010

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“…Such agents include the furocoumarins present in many plants (Scott et al 1976), nitrous acid in food (Edfeldt et al 2004); endogenous agents include products of lipid peroxidation, and nitric oxide (Caulfield et al 2003; Schärer 2005). Further research is warranted towards development of methods to detect the formation and repair of crosslinks caused by these agents in cells.…”

Section: Interstrand Crosslinks and Their Significancementioning

confidence: 99%

Mammalian nucleotide excision repair proteins and interstrand crosslink repair

Wood

2010

Environ and Mol Mutagen

113

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Although various schemes for interstrand crosslink (ICL) repair incorporate recombination, replication, and double-strand break intermediate steps, action of the NER system or some variation of it is a common feature of most models. In the bacterium Escherichia coli, the NER enzyme UvrABC can incise on either side of an ICL to unhook the crosslink, and repair can proceed via a subsequent recombination step. The relevance of NER to ICL repair in mammalian cells has been challenged. Of all NER mutants, it is clear that ERCC1 and XPF-defective cells show the most pronounced sensitivities to ICL-inducing agents, and defects in ICL repair. However, there is good evidence that cells defective in NER proteins including XPA and XPG are also more sensitive than normal to ICL-inducing agents. These results are summarized here, together with evidence for defective crosslink removal in NER-defective cells. Studies of incision at sites of ICL by cell extracts and purified proteins have been done, but these studies are not all consistent with one another and further research is required.

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“…Inducible nitric oxide synthase (iNOS) was shown as a significant source of ROS in the streptozotocin-induced diabetic rats [23]. Nitrous acid is also effective in the formation of DNA-protein crosslinks through oxidative modification of guanine residues [26–29]. …”

Section: Reactive Oxygen and Nitrogen Speciesmentioning

confidence: 99%

Oxidative Stress in Diabetes and Alzheimer's Disease

Reddy

Zhu

Perry

et al. 2009

JAD

237

145

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Oxidative stress plays a major role in diabetes as well as in Alzheimer's disease and other related neurological diseases. Intracellular oxidative stress arises due to the imbalance in the production of reactive oxygen/reactive nitrogen species and cellular antioxidant defense mechanisms. In turn, the excess reactive oxygen/reactive nitrogen species mediate the damage of proteins and nucleic acids, which have been shown to have direct and deleterious consequences in diabetes and Alzheimer's disease. Oxidative stress also contributes to the production of advanced glycation end products through glycoxidation and lipid peroxidation. The advanced glycation end products and lipid peroxidation products are ubiquitous to diabetes and Alzheimer's disease and serve as markers of disease progression in both disorders. Antioxidants and advanced glycation end products inhibitors, either induced endogenously or exogenously introduced, may counteract with the deleterious effects of the reactive oxygen/reactive nitrogen species and thereby, in prevention or treatment paradigms, attenuate or substantially delay the onset of these devastating pathologies.

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Solution structure of a nitrous acid induced DNA interstrand cross-link

Cited by 33 publications

References 41 publications

Cross-Link Structure Affects Replication-Independent DNA Interstrand Cross-Link Repair in Mammalian Cells

Cross-Link Structure Affects Replication-Independent DNA Interstrand Cross-Link Repair in Mammalian Cells

Mammalian nucleotide excision repair proteins and interstrand crosslink repair

Oxidative Stress in Diabetes and Alzheimer's Disease

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