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...
The repair of singlet oxygen (1O2)-induced DNA lesions requires several enzymes of the nucleotide and base excision repair pathways, including exonuclease III and endonuclease IV that are known apurinic/apyrimidinic-endonucleases in Escherichia coli. In order to better understand the relevance of exonuclease III on the repair of these lesions, we investigated the mutagenic events that result from the replication of a 1O2-damaged plasmid in an exonuclease-deficient host (xth). The mutation spectrum in the tRNA supF gene target indicated that the absence of exonuclease III does not change the types of mutations induced by 1O2 (mostly of G:C-->T:A and G:C-->C:G transversions). However, the spectrum shows that the mutations are scattered in the supF gene, which is significatively different from the one obtained in wild-type bacteria. Thus, exonuclease III may act on the repair of 1O2-induced lesions altering the DNA repair sequence specificity.
Cockayne syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachectic dwarfism, retinal atrophy, and progressive neurodegeneration. The molecular defect in CS lies in genes associated with the transcription-coupled branch of the nucleotide excision DNA repair (NER) pathway, though it is not yet clear how DNA repair deficiency leads to the multiorgan dysfunction symptoms of CS. In this work, we used a mouse model of severe CS with complete loss of NER ( Csa−/−/Xpa−/− ), which recapitulates several CS-related phenotypes, resulting in premature death of these mice at approximately 20 weeks of age. Although this CS model exhibits a severe progeroid phenotype, we found no evidence of in vitro endothelial cell dysfunction, as assessed by measuring population doubling time, migration capacity, and ICAM-1 expression. Furthermore, aortas from CX mice did not exhibit early senescence nor reduced angiogenesis capacity. Despite these observations, CX mice presented blood brain barrier disruption and increased senescence of brain endothelial cells. This was accompanied by an upregulation of inflammatory markers in the brains of CX mice, such as ICAM-1, TNFα, p-p65, and glial cell activation. Inhibition of neovascularization did not exacerbate neither astro- nor microgliosis, suggesting that the pro-inflammatory phenotype is independent of the neurovascular dysfunction present in CX mice. These findings have implications for the etiology of this disease and could contribute to the study of novel therapeutic targets for treating Cockayne syndrome patients.
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