Balancing repair and tolerance of DNA damage caused by alkylating agents

Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D.

doi:10.1038/nrc3185

Cited by 807 publications

(972 citation statements)

References 191 publications

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“…1A). Thus, if BER is initiated under conditions where subsequent processing of BER intermediates is limiting, this can result in cell death and tissue damage; under these circumstances, cells are said to have an imbalanced BER pathway (6). Having shown that Aag in WT mice stimulates more I/R-induced liver toxicity than that seen in Aag −/− mice, we determined whether this toxicity correlates with the accumulation of BER intermediates.…”

Section: Significancementioning

confidence: 99%

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Ebrahimkhani

Daneshmand

Mazumder

et al. 2014

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

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Inflammation is accompanied by the release of highly reactive oxygen and nitrogen species (RONS) that damage DNA, among other cellular molecules. Base excision repair (BER) is initiated by DNA glycosylases and is crucial in repairing RONS-induced DNA damage; the alkyladenine DNA glycosylase (Aag/Mpg) excises several DNA base lesions induced by the inflammation-associated RONS release that accompanies ischemia reperfusion (I/R). Using mouse I/R models we demonstrate that Aag −/− mice are significantly protected against, rather than sensitized to, I/R injury, and that such protection is observed across three different organs. Following I/R in liver, kidney, and brain, Aag −/− mice display decreased hepatocyte death, cerebral infarction, and renal injury relative to wild-type. We infer that in wild-type mice, Aag excises damaged DNA bases to generate potentially toxic abasic sites that in turn generate highly toxic DNA strand breaks that trigger poly (ADP-ribose) polymerase (Parp) hyperactivation, cellular bioenergetics failure, and necrosis; indeed, steady-state levels of abasic sites and nuclear PAR polymers were significantly more elevated in wild-type vs. Aag −/− liver after I/R. This increase in PAR polymers was accompanied by depletion of intracellular NAD and ATP levels plus the translocation and extracellular release of the high-mobility group box 1 (Hmgb1) nuclear protein, activating the sterile inflammatory response. We thus demonstrate the detrimental effects of Aag-initiated BER during I/R and sterile inflammation, and present a novel target for controlling I/R-induced injury.DNA repair | base excision | Aag/Mpg DNA glycosylase | ischemia reperfusion | liver

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Section: Significancementioning

confidence: 99%

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Ebrahimkhani

Daneshmand

Mazumder

et al. 2014

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

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“…Left unrepaired, these lesions have the potential to alter cellular function and compromise the health of the organism, leading to degenerative diseases, cancer, and premature aging (1)(2)(3)(4)(5). Consequently, interindividual variations in DNA repair capacity (DRC) are thought to contribute to the fact that people have different susceptibilities to these diseases (6)(7)(8)(9)(10).…”

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confidence: 99%

Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis

Nagel

Margulies

Chaim

et al. 2014

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

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The capacity to repair different types of DNA damage varies among individuals, making them more or less susceptible to the detrimental health consequences of damage exposures. Current methods for measuring DNA repair capacity (DRC) are relatively labor intensive, often indirect, and usually limited to a single repair pathway. Here, we describe a fluorescence-based multiplex flow-cytometric host cell reactivation assay (FM-HCR) that measures the ability of human cells to repair plasmid reporters, each bearing a different type of DNA damage or different doses of the same type of DNA damage. FM-HCR simultaneously measures repair capacity in any four of the following pathways: nucleotide excision repair, mismatch repair, base excision repair, nonhomologous end joining, homologous recombination, and methylguanine methyltransferase. We show that FM-HCR can measure interindividual DRC differences in a panel of 24 cell lines derived from genetically diverse, apparently healthy individuals, and we show that FM-HCR may be used to identify inhibitors or enhancers of DRC. We further develop a next-generation sequencing-based HCR assay (HCR-Seq) that detects rare transcriptional mutagenesis events due to lesion bypass by RNA polymerase, providing an added dimension to DRC measurements. FM-HCR and HCR-Seq provide powerful tools for exploring relationships among global DRC, disease susceptibility, and optimal treatment.

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“…NMPs are repaired by the multi-step base excision repair (BER) pathway. In human cells, the BER process is initiated by human alkyladenine glycosylase (hAAG), which recognizes and excises the methylated purine bases (1). The apurinic/apyrimidinic (AP) sites formed are typically recognized by an AP endonuclease that cleaves the DNA on the 5Ј side of the AP sites.…”

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confidence: 99%

“…methyl donors such as S-adenosylmethionine (1). Simple S N 2 methylating agents, such as dimethyl sulfate (DMS), 2 produce a variety of damaged bases in DNA, of which N-methylpurines (NMPs), including N 7 -methylguanine (7MeG) and N 3 -methyladenine (3MeA), constitute ϳ90% of the lesions (2).…”

mentioning

confidence: 99%

High-resolution Digital Mapping of N-Methylpurines in Human Cells Reveals Modulation of Their Induction and Repair by Nearest-neighbor Nucleotides

2015

Journal of Biological Chemistry

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Background: N-Methylpurines are repaired by the base excision repair pathway. Results: Induction and repair of N-methylpurines in human cells is significantly affected by nearest-neighbor nucleotides. Conclusion: Modulation of N-methylpurine repair by nearest-neighbor nucleotides is primarily achieved by affecting the initial step of the base excision repair process. Significance: Excision of N-methylpurines by alkyladenine glycosylase is most dramatically affected by sequence context.

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Balancing repair and tolerance of DNA damage caused by alkylating agents

Cited by 807 publications

References 191 publications

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis

High-resolution Digital Mapping of N-Methylpurines in Human Cells Reveals Modulation of Their Induction and Repair by Nearest-neighbor Nucleotides

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