Phosphorylation of human oxoguanine DNA glycosylase ( -OGG1) modulates its function

Hu, Jingping; Imam, Syed Z.; Hashiguchi, Kazunari; Souza-Pinto, Nadja C. de; Bohr, Vilhelm A.

doi:10.1093/nar/gki636

Cited by 66 publications

(55 citation statements)

References 49 publications

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“…Another possibility is that their biological roles are differentiated on the basis of post-translational modifications. For example, OGG1 serine-phosphorylation by protein kinase C modulates its intracellular localization (40), whereas its serine/threonine phosphorylation by cyclin-dependent kinase 4 (cdk4) modulates its catalytic properties (41).…”

Section: Discussionmentioning

confidence: 99%

Repair of Formamidopyrimidines in DNA Involves Different Glycosylases

Souza-Pinto

Haraguchi

et al. 2005

Journal of Biological Chemistry

181

148

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The oxidatively induced DNA lesions 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 4,6-diamino-5-formamidopyrimidine (FapyA) are formed abundantly in DNA of cultured cells or tissues exposed to ionizing radiation or to other free radical-generating systems. In vitro studies indicate that these lesions are miscoding, can block the progression of DNA polymerases, and are substrates for base excision repair. However, no study has yet addressed how these lesions are metabolized in cellular extracts. The synthesis of oligonucleotides containing FapyG and FapyA at defined positions was recently reported. These constructs allowed us to investigate the repair of Fapy lesions in nuclear and mitochondrial extracts from wild type and knock-out mice lacking the two major DNA glycosylases for repair of oxidative DNA damage, OGG1 and NTH1. The background level of FapyG/FapyA in DNA from these mice was also determined. Endogenous FapyG levels in liver DNA from wild type mice were significantly higher than 8-hydroxyguanine levels. FapyG and FapyA were efficiently repaired in nuclear and mitochondrial extracts from wild type animals but not in the glycosylasedeficient mice. Our results indicated that OGG1 and NTH1 are the major DNA glycosylases for the removal of FapyG and FapyA, respectively. Tissue-specific analysis suggested that other DNA glycosylases may contribute to FapyA repair when NTH1 is poorly expressed. We identified NEIL1 in liver mitochondria, which could account for the residual incision activity in the absence of OGG1 and NTH1. FapyG and FapyA levels were significantly elevated in DNA from the knock-out mice, underscoring the biological role of OGG1 and NTH1 in the repair of these lesions.A large number of DNA base modifications are formed by oxidative damage to DNA (for review, see Ref. 1). Some of these lesions are generated at high rates, even in the absence of exogenous DNA-damaging agents. For instance, it was estimated that 100 -500 8-hydroxyguanines 3 are formed per day in a human cell (2). 8-oxoG is one of the most studied DNA lesions, and it is often used as a biomarker of oxidative DNA damage. However, ring-opened formamidopyrimidine lesions, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 4,6-diamino-5-formamidopyrimidine (FapyA), are formed at equal or higher levels than 8-oxoG after oxidative stress (3-5). These lesions result from hydroxyl radical attack on guanine and adenine, respectively, followed by one-electron reduction of the hydroxyl adduct radicals (1), which are also intermediates in the formation of 8-oxoG and 8-oxoA (6). Formation of Fapy lesions in DNA upon UV radiation has also been reported (7). FapyA (8) and FapyG (9) are miscoding in vitro, both directing the preferential misincorporation of adenine opposite the lesions by a bacterial DNA polymerase (Klenow exo Ϫ ). Experiments using the methylated analogue of FapyG, i.e. 2,6-diamino-4-hydroxy-5-Nmethylformamidopyrimidine (Me-FapyG), have suggested that formamidopyrimidines might also constitute blocks to DNA poly...

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Section: Discussionmentioning

confidence: 99%

Repair of Formamidopyrimidines in DNA Involves Different Glycosylases

Souza-Pinto

Haraguchi

et al. 2005

Journal of Biological Chemistry

181

148

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“…5Ј-End labeling was carried out using T4 polynucleotides kinase (New England Biolabs) and [␥- Cell culture. HEK293 cells (from the American Type Culture Collection) harboring OGG1-␣-FLAG or the empty vector were described earlier (16). The cells were grown in Dulbecco modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (Gibco-BRL) and 800 g of Geneticin (Invitrogen)/ml at 37°C under an atmosphere of 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

The Recombination Protein RAD52 Cooperates with the Excision Repair Protein OGG1 for the Repair of Oxidative Lesions in Mammalian Cells

Souza-Pinto

Maynard

Hashiguchi

et al. 2009

Molecular and Cellular Biology

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Oxidized bases are common types of DNA modifications. Their accumulation in the genome is linked to aging and degenerative diseases. These modifications are commonly repaired by the base excision repair (BER) pathway. Oxoguanine DNA glycosylase (OGG1) initiates BER of oxidized purine bases. A small number of protein interactions have been identified for OGG1, while very few appear to have functional consequences. We report here that OGG1 interacts with the recombination protein RAD52 in vitro and in vivo. This interaction has reciprocal functional consequences as OGG1 inhibits RAD52 catalytic activities and RAD52 stimulates OGG1 incision activity, likely increasing its turnover rate. RAD52 colocalizes with OGG1 after oxidative stress to cultured cells, but not after the direct induction of double-strand breaks by ionizing radiation. Human cells depleted of RAD52 via small interfering RNA knockdown, and mouse cells lacking the protein via gene knockout showed increased sensitivity to oxidative stress. Moreover, cells depleted of RAD52 show higher accumulation of oxidized bases in their genome than cells with normal levels of RAD52. Our results indicate that RAD52 cooperates with OGG1 to repair oxidative DNA damage and enhances the cellular resistance to oxidative stress. Our observations suggest a coordinated action between these proteins that may be relevant when oxidative lesions positioned close to strand breaks impose a hindrance to RAD52 catalytic activities.Oxidative DNA damage is generated at high levels in mammalian cells, even in cells not exposed to exogenous sources of reactive oxygen species. Several kinds of DNA modifications are formed upon oxidative stress (8). The most prevalent modifications, quantitatively, are single-strand breaks and oxidized bases. Clustered DNA damage, when two or more modifications are closely positioned in opposite strands, is detectable after gamma irradiation and has recently been shown to be generated by normal oxidative metabolism (3,35). One unique aspect of such clustered lesions is that they can be converted into double-strand breaks (DSB) if a DNA glycosylase removes the two opposite bases and an apurinic/apyrimidinic (AP)-endonuclease cleaves the resulting abasic sites. Thus, although quantitatively minor, DSB are possible outcomes of oxidative DNA damage.

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“…Recently, post-translational phosphorylations of OGG1, the predominant glycosylase for oxidative damage, have been reported [96]. Two independent kinases were shown to phosphorylate OGG1 in vitro [96]. C-Abl-mediated phosphorylation of hOGG1 had no effect on activity.…”

Section: Modification Of Proteins That Initiate Ber Via Lesion Recognmentioning

confidence: 99%

“…This could be the result of cellular signaling cascades that are designed to activate checkpoint pathways and thus prevent the cell from proceeding with cell division while simultaneously enhancing DNA repair. Recently, post-translational phosphorylations of OGG1, the predominant glycosylase for oxidative damage, have been reported [96]. Two independent kinases were shown to phosphorylate OGG1 in vitro [96].…”

Section: Modification Of Proteins That Initiate Ber Via Lesion Recognmentioning

confidence: 99%

See 1 more Smart Citation

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

385

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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Phosphorylation of human oxoguanine DNA glycosylase ( -OGG1) modulates its function

Cited by 66 publications

References 49 publications

Repair of Formamidopyrimidines in DNA Involves Different Glycosylases

Repair of Formamidopyrimidines in DNA Involves Different Glycosylases

The Recombination Protein RAD52 Cooperates with the Excision Repair Protein OGG1 for the Repair of Oxidative Lesions in Mammalian Cells

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

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