A basal-level activity of ATR links replication fork surveillance and stress response.
Mol Cell
; 81(20): 4243-4257.e6, 2021 10 21.
Article
in En
| MEDLINE
| ID: mdl-34473946
ABSTRACT
Mammalian cells use diverse pathways to prevent deleterious consequences during DNA replication, yet the mechanism by which cells survey individual replisomes to detect spontaneous replication impediments at the basal level, and their accumulation during replication stress, remain undefined. Here, we used single-molecule localization microscopy coupled with high-order-correlation image-mining algorithms to quantify the composition of individual replisomes in single cells during unperturbed replication and under replicative stress. We identified a basal-level activity of ATR that monitors and regulates the amounts of RPA at forks during normal replication. Replication-stress amplifies the basal activity through the increased volume of ATR-RPA interaction and diffusion-driven enrichment of ATR at forks. This localized crowding of ATR enhances its collision probability, stimulating the activation of its replication-stress response. Finally, we provide a computational model describing how the basal activity of ATR is amplified to produce its canonical replication stress response.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA, Neoplasm
/
DNA Replication
/
Ataxia Telangiectasia Mutated Proteins
Type of study:
Prognostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2021
Document type:
Article