M. M. Iii: (D) North Quarter and Entrance

Evans, Arthur

doi:10.1017/cbo9781139795005.022

Cited by 59 publications

(98 citation statements)

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“…Hydroxyl radicals attack DNA bases and the sugar-phosphate DNA backbone, generating modified bases and singlestranded DNA (ssDNA) breaks, respectively (11). Many oxida-tively induced DNA lesions are mutagenic and/or cytotoxic and have been associated with aging, neurodegeneration, and carcinogenesis (for review, see Refs.…”

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“…This lesion, however, may be a weak mutagen in vivo because it can be faithfully bypassed in the presence of proliferating cell nuclear antigen and replication protein A (25). Formamidopyrimidines (Fapys) 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) and 4,6-diamino-5-formamidopyrimidine (FapyAde) are imidazole ring-opened products of purines which share a common intermediate with 8-OHGua and 7,8-dihydro-8-oxoadenine, respectively (11,26). FapyGua and FapyAde are the main substrates of human and mouse NEIL1 (27)(28)(29) and are detected in genomic DNA at a higher level than 8-OH-Gua (30), suggesting that accumulation of these lesions may be of importance in the development of the severe phenotype observed in neil1 Ϫ/Ϫ mice.…”

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Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase

Müftüoğlu

Souza-Pinto

Doğan

et al. 2009

Journal of Biological Chemistry

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Cockayne syndrome (CS) 6 is a segmental premature aging syndrome with progressive neurological degeneration (1). CS is caused by mutations in CS complementation groups A (CSA) or B (CSB) genes (2, 3). Approximately 80% of CS patients have mutations in the CSB gene, which encodes a 168-kDa protein belonging to the SWI/SNF2 family of chromatin remodeling proteins (4). Cells from CS patients are hypersensitive to UV radiation-induced DNA damage, and the CSB protein is required for the transcription-coupled nucleotide excision repair of UV radiation-induced DNA lesions (cyclobutane pyrimidine dimers and 6-pyrimidine-4-pyrimidone products) (5). CSB is also believed to play a role in transcription elongation and interacts with the RNA polymerase II elongation complex (6). The molecular basis of the progressive neurological defects in CS patients, however, remains unknown; it has been proposed that neurological symptoms in CS may be due to defective repair and/or processing of oxidative DNA damage in CSB-deficient cells (7).Oxidative DNA damage can be caused by endogenous and exogenous agents. Reactive oxygen species, including highly reactive hydroxyl radicals, are formed as byproducts of normal metabolism, mostly during the process of mitochondrial respiration. It has been estimated that up to 2% of all the O 2 consumed by respiration may be released as reactive oxygen species (8, 9). The central nervous system relies exclusively on mitochondria to generate ATP through oxidative metabolism. As a result, neurons are susceptible to increased levels of oxidative stress, and elevated levels of reactive oxygen species have been implicated in the etiology of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington diseases and amyotrophic lateral sclerosis (for a review, see Ref. 10).Hydroxyl radicals attack DNA bases and the sugar-phosphate DNA backbone, generating modified bases and singlestranded DNA (ssDNA) breaks, respectively (11). Many oxida-

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confidence: 99%

Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase

Müftüoğlu

Souza-Pinto

Doğan

et al. 2009

Journal of Biological Chemistry

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“…purine lesions are 8-oxoguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 4,6-diamino-5-formamidopyrimidine (1)(2)(3)(4)(5). To reverse the potentially deleterious effects of oxidative DNA base lesions, cells primarily use the base excision repair (BER) pathway to restore the DNA to its undamaged state (6).…”

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The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Vartanian

Lowell

Minko

et al. 2006

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

224

221

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Endogenously formed reactive oxygen species continuously damage cellular constituents including DNA. These challenges, coupled with exogenous exposure to agents that generate reactive oxygen species, are both associated with normal aging processes and linked to cardiovascular disease, cancer, cataract formation, and fatty liver disease. Although not all of these diseases have been definitively shown to originate from mutations in nuclear DNA or mitochondrial DNA, repair of oxidized, saturated, and ring-fragmented bases via the base excision repair pathway is known to be critical for maintaining genomic stability. One enzyme that initiates base excision repair of ring-fragmented purines and some saturated pyrimidines is NEIL1, a mammalian homolog to Escherichia coli endonuclease VIII. To investigate the organismal consequences of a deficiency in NEIL1, a knockout mouse model was created. In the absence of exogenous oxidative stress, neil1 knockout (neil1 ؊/؊ ) and heterozygotic (neil1 ؉/؊ ) mice develop severe obesity, dyslipidemia, and fatty liver disease and also have a tendency to develop hyperinsulinemia. In humans, this combination of clinical manifestations, including hypertension, is known as the metabolic syndrome and is estimated to affect >40 million people in the United States. Additionally, mitochondrial DNA from neil1 ؊/؊ mice show increased levels of steady-state DNA damage and deletions relative to wild-type controls. These data suggest an important role for NEIL1 in the prevention of the diseases associated with the metabolic syndrome.DNA repair ͉ fatty liver disease ͉ mitochondria ͉ obesity ͉ oxidative stress A fter exposure to reactive oxygen species (ROS), the major purine lesions are 8-oxoguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 4,6-diamino-5-formamidopyrimidine (1-5). To reverse the potentially deleterious effects of oxidative DNA base lesions, cells primarily use the base excision repair (BER) pathway to restore the DNA to its undamaged state (6). The BER pathway is initiated by lesion-specific DNA glycosylases that catalyze bond scission and release the damaged base from the deoxyribose sugar.Unlike nucleotide excision repair, which functions only on nuclear DNA, the BER pathway is operative on both nuclear DNA and mitochondrial DNA (mtDNA). Although BER in the mitochondria repairs normal endogenous oxidant-induced DNA damage, expression of mitochondrially targeted DNA glycosylases that are specific for the repair of oxidatively induced DNA lesions leads to enhanced repair and increased survival after ROS challenge (7-10). These data emphasize that maintenance of the mitochondrial genome is a delicate balance of mtDNA copy number and BER capacity.To initiate repair of oxidative lesions, mammalian cells primarily use the products of the ogg1, nth1, neil1, and neil2 genes (11). These corresponding proteins have somewhat overlapping substrate specificities that may explain, at least partially, the absence of obvious phenotypes in ogg1-and nth1-null mice. NEIL1 has a strong sub...

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“…Os principais alvos de ROS incluem DNA, lipídeos, proteínas e açúcares, sendo que a ordem de preferência de ataque depende de muitos fatores, como o local onde a espécie reativa é gerada, a habilidade relativa de uma biomolécula ser oxidada e a disponibilidade de íons metálicos associados a essa biomolécula 3 . No entanto, enquanto lipídeos, proteínas e açúcares podem ser removidos via degradação, o mesmo não deve ocorrer com o DNA, uma vez que é a molécula responsável por todas as informações genéticas de todas as células de um organismo vivo.…”

Section: Introductionunclassified

Estresse oxidativo, lesões no genoma e processos de sinalização no controle do ciclo celular

Berra¹,

Menck²,

Mascio³

2006

Quím. Nova

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Recebido em 21/2/05; aceito em 16/12/05; publicado na web em 1/8/06 OXIDATIVE STRESS, GENOME LESIONS AND SIGNALING PATHWAYS IN CELL CYCLE CONTROL. The generation of reactive oxygen species (ROS) may be both beneficial to cells, performing functions in intracellular signaling and detrimental, modifying cellular biomolecules. ROS can cause DNA damage, such as base damage and strand breaks. Organisms respond to chromosome insults by activation of a complex and hierarchical DNA-damage response pathway. The extent of DNA damages determines cell fate: cell cycle arrest and DNA repair or cell death. The ATM is a central protein in the response to DNA double-strand breaks by acting as a transducer protein. Collected evidences suggest that ATM is also involved in the response to oxidative DNA damage.Keywords: ATM; checkpoints; oxidative stress. INTRODUÇÃOAs células vivas presentes em uma atmosfera rica em oxigênio estão constantemente expostas aos possíveis danos causados por espécies reativas de oxigênio (ROS -"reactive oxygen species"), que podem ser originadas tanto exógena quanto endogenamente. As fontes exógenas de ROS incluem luz ultravioleta (UV) principalmente nos comprimentos de onda maiores que 280 nm -UVA e UVB, irradiação ionizante e agentes químicos. Já as ROS formadas intracelularmente podem ser originadas como conseqüência do pró-prio metabolismo celular, uma vez que elétrons provenientes da cadeia de transportes de elétrons, localizada na mitocôndria, podem interagir com várias moléculas intracelulares. ROS são também produzidas durante processos patológicos, como, por ex., o que ocorre em uma resposta inflamatória celular.É importante salientar que ROS nem sempre são consequência do metabolismo celular, mas podem ser também geradas pelas oxidases (enzimas específicas da membrana plasmática) como resposta a fatores de crescimento e citocinas e, conseqüentemente, podem servir como segundo mensageiro em alguns processos específicos de sinalização celular 1 . Em geral, deve-se notar que a geração intracelular de ROS, considerada normal em níveis fisiológicos, quando não é necessariamente lesiva, tem um importante papel vital, uma vez que essas espé-cies, nesses casos produzidas de forma controlada, atuam na regulação da sinalização celular e da expressão gênica ), mas também derivados do oxigênio que não são radicais, como peróxido de hidrogênio (H 2 O 2 ), ácido hipocloroso (HOCl), ozônio (O 3 ) e oxigênio singlete ( 1 O 2 ) 2 , exemplificados na Tabela 1. Evolutivamente, foram selecionadas várias estratégias antioxidantes para as células lidarem com a toxicidade do oxigênio. Os agentes considerados como antioxidantes compreendem: enzimas que removem cataliticamente radicais e espécies reativas, como por ex., as enzimas superóxido dismutase (SOD), glutationa redutase, glutationa peroxidase e catalases (Tabela 1); proteínas que minimizam a disponibilidade de pró-oxidantes, tais como íons ferro e íons cobre, como por ex., as transferrinas, ferritinas, metalotioneinas e haptoglobinas; proteínas que protegem pr...

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M. M. Iii: (D) North Quarter and Entrance

Cited by 59 publications

References 0 publications

Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase

Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase

The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Estresse oxidativo, lesões no genoma e processos de sinalização no controle do ciclo celular

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