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ATR autophosphorylation as a molecular switch for checkpoint activation.
Liu, Shizhou; Shiotani, Bunsyo; Lahiri, Mayurika; Maréchal, Alexandre; Tse, Alice; Leung, Charles Chung Yun; Glover, J N Mark; Yang, Xiaohong H; Zou, Lee.
Afiliación
  • Liu S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Mol Cell ; 43(2): 192-202, 2011 Jul 22.
Article en En | MEDLINE | ID: mdl-21777809
ABSTRACT
The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master checkpoint regulator safeguarding the genome. Upon DNA damage, the ATR-ATRIP complex is recruited to sites of DNA damage by RPA-coated single-stranded DNA and activated by an elusive process. Here, we show that ATR is transformed into a hyperphosphorylated state after DNA damage, and that a single autophosphorylation event at Thr 1989 is crucial for ATR activation. Phosphorylation of Thr 1989 relies on RPA, ATRIP, and ATR kinase activity, but unexpectedly not on the ATR stimulator TopBP1. Recruitment of ATR-ATRIP to RPA-ssDNA leads to congregation of ATR-ATRIP complexes and promotes Thr 1989 phosphorylation in trans. Phosphorylated Thr 1989 is directly recognized by TopBP1 via the BRCT domains 7 and 8, enabling TopBP1 to engage ATR-ATRIP, to stimulate the ATR kinase, and to facilitate ATR substrate recognition. Thus, ATR autophosphorylation on RPA-ssDNA is a molecular switch to launch robust checkpoint response.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Proteínas de Ciclo Celular Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Proteínas de Ciclo Celular Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos