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1.
DNA Repair (Amst) ; 1(10): 779-93, 2002 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12531026

RESUMO

Homologous recombination is one of the major pathways for repair of DNA double-strand breaks (DSBs). Important proteins in this pathway are Rad51 and Rad54. Rad51 forms a nucleoprotein filament on single-stranded DNA (ssDNA) that mediates pairing with and strand invasion of homologous duplex DNA with the assist of Rad54. We estimated that the nucleus of a mouse embryonic stem (ES) cells contains on average 4.7x10(5) Rad51 and 2.4x10(5) Rad54 molecules. Furthermore, we showed that the amount of Rad54 was subject to cell cycle regulation. We discuss our results with respect to two models that describe how Rad54 stimulates Rad51-mediated DNA strand invasion. The models differ in whether Rad54 functions locally or globally. In the first model, Rad54 acts in cis relative to the site of strand invasion. Rad54 coats the Rad51 nucleoprotein filament in stoichiometric amounts and binds to the target duplex DNA at the site that is homologous to the ssDNA in the Rad51 nucleoprotein filament. Subsequently, it promotes duplex DNA unwinding. In the second model, Rad54 acts in trans relative to the site of strand invasion. Rad54 binds duplex DNA distant from the site that will be unwound. Translocation of Rad54 along the duplex DNA increases superhelical stress thereby promoting duplex DNA unwinding.


Assuntos
Reparo do DNA/fisiologia , Recombinação Genética/genética , Proteínas de Saccharomyces cerevisiae/fisiologia , Animais , Ciclo Celular/fisiologia , Núcleo Celular/genética , Núcleo Celular/metabolismo , DNA Helicases , Enzimas Reparadoras do DNA , DNA de Cadeia Simples , DNA Super-Helicoidal/metabolismo , Escherichia coli , Citometria de Fluxo , Immunoblotting , Hibridização In Situ , Camundongos , Células-Tronco Pluripotentes/metabolismo , Regiões Promotoras Genéticas , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
2.
DNA Repair (Amst) ; 1(2): 143-57, 2002 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-12509261

RESUMO

Cockayne syndrome (CS) is an inherited photosensitive neurodevelopmental disorder caused by a specific defect in the transcription-coupled repair (TCR) sub-pathway of NER. Remarkably, despite their DNA repair deficiency, CS patients do not develop skin cancer. Here, we present a mouse model for CS complementation group A. Like cells from CS-A patients, Csa-/- mouse embryonic fibroblasts (MEFs): (i) are ultraviolet (UV)-sensitive; (ii) show normal unscheduled DNA synthesis (indicating that the global genome repair sub-pathway is unaffected); (iii) fail to resume RNA synthesis after UV-exposure and (iv) are unable to remove cyclobutane pyrimidine dimers (CPD) photolesions from the transcribed strand of active genes. CS-A mice exhibit UV-sensitivity and pronounced age-dependent loss of retinal photoreceptor cells but otherwise fail to show the severe developmental and neurological abnormalities of the human syndrome. In contrast to human CS, Csa-/- animals develop skin tumors after chronic exposure to UV light, indicating that TCR in mice protects from UV-induced skin cancer development. Strikingly, inactivation of one Xpc allele (encoding a component of the damage recognition complex involved in the global genome repair sub-pathway) in Csa-/- mice resulted in a strongly enhanced UV-mediated skin cancer sensitivity, indicating that in a TC repair defective background, the Xpc gene product may be a rate-limiting factor in the removal of UV-induced DNA lesions.


Assuntos
Síndrome de Cockayne/genética , Reparo do DNA/fisiologia , Neoplasias Induzidas por Radiação/genética , Proteínas/genética , Sequência de Aminoácidos , Animais , Síndrome de Cockayne/etiologia , Síndrome de Cockayne/patologia , Dano ao DNA , Reparo do DNA/efeitos da radiação , Enzimas Reparadoras do DNA , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos da radiação , Teste de Complementação Genética , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/patologia , Proteínas/metabolismo , RNA/genética , RNA/metabolismo , Homologia de Sequência de Aminoácidos , Pele/efeitos da radiação , Neoplasias Cutâneas/etiologia , Fatores de Transcrição , Raios Ultravioleta
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