Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage

Izumi, Tohru; Wiederhold, Lee; Roy, Gargi; Roy, Rabindra; Jaiswal, Arun Kumar; Bhakat, Kishor K.; Mitra, Sankar; Hazra, Tapas K.

doi:10.1016/s0300-483x(03)00289-0

Cited by 191 publications

(158 citation statements)

References 166 publications

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“…We had shown earlier that APE1 activity is limiting in repair of ROS-induced strand breaks but not of AP sites [123]. Using embryonic fibroblast line with conditional null mutation of APE1, we observed that APE1 npg inactivation led to significant increase in single-strand breaks as well as AP sites [112,124].…”

Section: Accumulation Of Single-strand Breaks In the Genome Of Ape1-nmentioning

confidence: 67%

“…This segment contains the nuclear localization signal (NLS) [110] and is also required for the transcriptional regulation function unique to APE1 and unrelated to BER [111,112]. We recently discovered that human APE1 (hAPE1) is acetylated in vivo at Lys 6 / Lys 7 which modulates its regulatory but not endonuclease activity [113].…”

Section: Mammalian Ape1 and E Coli Xth Have Distinct Propertiesmentioning

confidence: 99%

“…The broad view of BER in the last decade was that of a sequential process in which individual repair enzymes carried out reactions independently of one another [112]. Based on the emerging evidence for the existence of the 'protein interactome', we propose a new paradigm in BER that postulates collaboration of multiple proteins in coordinated fashion involving specific protein-protein interactions to enhance the efficiency of repair.…”

Section: Repair Interactome -A New Paradigm In Bermentioning

confidence: 99%

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Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

2008

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Base excision repair (BER) is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged (oxidized or alkylated) or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species (ROS). BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease (APE) to generate 3′ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA ligase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APE1, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3′ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and ligases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organelle targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.

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Section: Accumulation Of Single-strand Breaks In the Genome Of Ape1-nmentioning

confidence: 67%

Section: Mammalian Ape1 and E Coli Xth Have Distinct Propertiesmentioning

confidence: 99%

Section: Repair Interactome -A New Paradigm In Bermentioning

confidence: 99%

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Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

2008

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“…Excision of 8-oxoG is initiated by OGG1, which recognizes and removes the base in a free form by cleavage of the glycosylic bond between the damaged base and the deoxyribose residue. The resulting abasic site is cleaved by AP endonuclease-1 to generate a gap that is filled by DNA polymerase followed by action of DNA ligase to complete the repair process [19,46]. Agarose gel analysis of the mtDNA samples indicated that the isolation procedure resulted in partial fragmentation of mtDNA, whereas antimycin A-treatment did not result in further detectable changes in mtDNA integrity, despite the fact that during repair of 8-oxoG in DNA transient single strand breaks are generated [47].…”

Section: Discussionmentioning

confidence: 99%

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Pázmándi

Agod

Kumar

et al. 2014

Free Radical Biology and Medicine

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Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j. freeradbiomed. 2014.09.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.www.elsevier.com/locate/freeradbiomed Abbreviations: 7-AAD, 7-aminoactinomycin-D; 8-oxoG, 8-oxo-7,8-dihydroguanine; 8-oxodG, 8-oxo-7,8-dihydro-2'- well as increased TNF-Į and IL-8 production from the cells. These effects were more apparent when pDCs were exposed to oxidatively modified mtDNA. Neither native nor oxidized mtDNA molecules were able to induce interferon (IFN)-Į secretion from pDCs unless they formed a complex with human cathelicidin LL-37, an antimicrobial peptide.Interestingly, simultaneous administration of a Toll-like receptor (TLR)9 antagonist abrogated the effects of both native and oxidized mtDNAs on human pDCs. In a murine model, oxidized mtDNA also proved a more potent activator of pDCs compared to the native form, except for induction of IFN-Į production. Collectively, we demonstrate here for the first time that elevated levels of 8-oxoG bases in the extracellular mtDNA induced by oxidative stress increase the immunostimulatory capacity of mtDNA on pDCs. 3 HighlightsWe compared the immunostimulatory capacity of native and oxidized mtDNA on pDCs.8-Oxoguanin-containing mtDNA has a greater capacity to activate primary human pDCs.In vivo, oxidized mtDNA also proved a more potent activator of pDC than native mtDNA.

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“…Several glycosylases have been identified with the ability to remove oxidative base damage, including thymine glycol DNA glycosylase, hydroxymethyl uracil glycosylase, and 8-oxodG DNA glycosylase. 12 The latter function is exerted by the human 8-oxoguanine DNA glycosylase (hOgg1), whose specificity for 8-oxo-dG is when formed in situ in DNA and hence paired opposite C. In Escherichia coli, formamidopyrimidine-DNA glycosylase (Fpg), a functional homologue of Ogg1 removes the 8-oxo-dG. 13 A second 8-oxodG glycosylase, namely hOgg2, has a specificity for 8-oxo-dG when derived from the nucleotide pool and misincorporated opposite G or A.…”

Section: Introductionmentioning

confidence: 99%

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

et al. 2005

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It is unknown whether base excision DNA repair (BER) proteins interact with mitogen-activated protein kinases (MAPK) under oxidation. Here, we explored roles of BER proteins in signaling transduction involving MAPK during hyperoxia. We demonstrated that ERK1/2 phosphorylation in A549 cells was increased in 95% O 2 . p38 activity in A549 cells was also increased by exposure to 95% O 2 . To evaluate regulatory roles of MAPK, we have transduced A549 cells and primary alveolar epithelial type II cells (AECII) to overexpress 8-oxoguanine DNA glycosylase (hOgg1). Overexpression of hOgg1 reduced hyperoxic toxicity in A549 and AECII cells. Furthermore, protection by BER against hyperoxia appeared to involve an upregulation of ERK1/2 and downregulation of p38. These observations demonstrate, for the first time, that reduction of hyperoxic toxicity by BER proteins may be involved with MAPK activity, thereby impacting cell survival. Furthermore, our studies suggest that modulation of MAPK may be used in combination with BER proteins to counteract hyperoxic toxicity.

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Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage

Cited by 191 publications

References 166 publications

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity

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