A basal-level activity of ATR links replication fork surveillance and stress response
| Autor: | Peter Tonzi, Yandong Yin, Huijun Xue, Tony T. Huang, James A. Borowiec, Wei Ting C. Lee, Mauro Modesti, Eli Rothenberg, Dipika Gupta |
|---|---|
| Přispěvatelé: | Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
[SDV]Life Sciences [q-bio] Level activity Ataxia Telangiectasia Mutated Proteins Biology Article Fight-or-flight response 03 medical and health sciences Basal (phylogenetics) 0302 clinical medicine Cell Line Tumor Replication Protein A Replication (statistics) Image Processing Computer-Assisted Humans Phosphorylation Molecular Biology ComputingMilieux_MISCELLANEOUS 030304 developmental biology 0303 health sciences Replication stress Mechanism (biology) DNA replication DNA Neoplasm Cell Biology Single Molecule Imaging Cell biology Kinetics Checkpoint Kinase 1 Mutation Replisome Algorithms 030217 neurology & neurosurgery |
| Zdroj: | Molecular Cell Molecular Cell, Elsevier, 2021, 81 (20), pp.4243-4257.e6. ⟨10.1016/j.molcel.2021.08.009⟩ Mol Cell Molecular Cell, 2021, 81 (20), pp.4243-4257.e6. ⟨10.1016/j.molcel.2021.08.009⟩ |
| ISSN: | 1097-2765 1097-4164 |
| DOI: | 10.1016/j.molcel.2021.08.009⟩ |
| Popis: | Mammalian cells employ 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, remains undefined. Here, we utilized 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. |
| Databáze: | OpenAIRE |
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