A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells.
Elife
; 122023 08 30.
Article
en En
| MEDLINE
| ID: mdl-37647215
ABSTRACT
When replication forks encounter DNA lesions that cause polymerase stalling, a checkpoint pathway is activated. The ATR-dependent intra-S checkpoint pathway mediates detection and processing of sites of replication fork stalling to maintain genomic integrity. Several factors involved in the global checkpoint pathway have been identified, but the response to a single replication fork barrier (RFB) is poorly understood. We utilized the Escherichia coli-based Tus-Ter system in human MCF7 cells and showed that the Tus protein binding to TerB sequences creates an efficient site-specific RFB. The single fork RFB was sufficient to activate a local, but not global, ATR-dependent checkpoint response that leads to phosphorylation and accumulation of DNA damage sensor protein γH2AX, confined locally to within a kilobase of the site of stalling. These data support a model of local management of fork stalling, which allows global replication at sites other than the RFB to continue to progress without delay.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Replicación del ADN
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Elife
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos