DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response.
Nucleic Acids Res
; 42(7): 4463-73, 2014 Apr.
Article
en En
| MEDLINE
| ID: mdl-24500207
ABSTRACT
The ataxia telangiectasia mutated and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis is the major signaling pathway activated in response to replication stress and is essential for the intra-S checkpoint. ATR phosphorylates and activates a number of molecules to coordinate cell cycle progression. Chk1 is the major effector downstream from ATR and plays a critical role in intra-S checkpoint on replication stress. Activation of Chk1 kinase also requires its association with Claspin, an adaptor protein essential for Chk1 protein stability, recruitment and ATR-dependent Chk1 phosphorylation. We have previously reported that, on replication stress, the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is rapidly phosphorylated by ATR at the stalled replication forks and is required for cellular resistance to replication stresses although the impact of DNA-PKcs onto the ATR signaling pathway remains elusive. Here we report that ATR-dependent Chk1 phosphorylation and Chk1 signaling are compromised in the absence of DNA-PKcs. Our investigation reveals that DNA-PKcs is required to maintain Chk1-Claspin complex stability and transcriptional regulation of Claspin expression. The impaired Chk1 activity results in a defective intra-S checkpoint response in DNA-PKcs-deficient cells. Taken together, these results suggest that DNA-PKcs, in addition to its direct role in DNA damage repair, facilitates ATR-Chk1 signaling pathway in response to replication stress.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
/
Proteínas Nucleares
/
Proteínas Adaptadoras Transductoras de Señales
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Replicación del ADN
/
Proteína Quinasa Activada por ADN
Límite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2014
Tipo del documento:
Article
País de afiliación:
Japón