Dormant origin signaling during unperturbed replication.
DNA Repair (Amst)
; 81: 102655, 2019 09.
Article
en En
| MEDLINE
| ID: mdl-31311769
ABSTRACT
Mechanisms that limit origin firing are essential as the Ë50,000 origins that replicate the human genome in unperturbed cells are chosen from an excess of Ë500,000 licensed origins. Computational models of the spatiotemporal pattern of replication foci assume that origins fire stochastically with a domino-like progression that places later firing origins near recent fired origins. These stochastic models of origin firing require dormant origin signaling that inhibits origin firing and suppresses licensed origins for passive replication at a distance of â¼7-120 kbp around replication forks. ATR and CHK1 kinase inhibitors increase origin firing and increase origin density in unperturbed cells. Thus, basal ATR and CHK1 kinase-dependent dormant origin signaling inhibits origin firing and there appear to be two thresholds of ATR kinase signaling. A minority of ATR molecules are activated for ATR and CHK1 kinase-dependent dormant origin signaling and this is essential for DNA replication in unperturbed cells. A majority of ATR molecules are activated for ATR and CHK1 kinase-dependent checkpoint signaling in cells treated with DNA damaging agents that target replication forks. Since ATR and CHK1 kinase inhibitors increase origin firing and this is associated with fork stalling and extensive regions of single-stranded DNA, they are DNA damaging agents. Accordingly, the sequence of administration of ATR and CHK1 kinase inhibitors and DNA damaging agents may impact the DNA damage induced by the combination and the efficacy of cell killing by the combination.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Transducción de Señal
/
Replicación del ADN
/
Proteínas de la Ataxia Telangiectasia Mutada
/
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)
Límite:
Animals
/
Humans
Idioma:
En
Revista:
DNA Repair (Amst)
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Año:
2019
Tipo del documento:
Article