Dampening DNA damage checkpoint signalling via coordinated BRCT domain interactions.
EMBO J
; 34(12): 1704-17, 2015 Jun 12.
Article
em En
| MEDLINE
| ID: mdl-25896509
ABSTRACT
In response to DNA damage, checkpoint signalling protects genome integrity at the cost of repressing cell cycle progression and DNA replication. Mechanisms for checkpoint down-regulation are therefore necessary for proper cellular proliferation. We recently uncovered a phosphatase-independent mechanism for dampening checkpoint signalling, where the checkpoint adaptor Rad9 is counteracted by the repair scaffolds Slx4-Rtt107. Here, we establish the molecular requirements for this new mode of checkpoint regulation. We engineered a minimal multi-BRCT-domain (MBD) module that recapitulates the action of Slx4-Rtt107 in checkpoint down-regulation. MBD mimics the damage-induced Dpb11-Slx4-Rtt107 complex by synergistically interacting with lesion-specific phospho-sites in Ddc1 and H2A. We propose that efficient recruitment of Dpb11-Slx4-Rtt107 or MBD via a cooperative 'two-site-docking' mechanism displaces Rad9. MBD also interacts with the Mus81 nuclease following checkpoint dampening, suggesting a spatio-temporal coordination of checkpoint signalling and DNA repair via a combinatorial mode of BRCT-domains interactions.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Proteínas Recombinantes
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Proteínas Nucleares
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Transdução de Sinais
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Proteínas de Saccharomyces cerevisiae
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Pontos de Checagem do Ciclo Celular
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Modelos Biológicos
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos