ATR Contributes More Than ATM in Intra-S-Phase Checkpoint Activation after IR, and DNA-PKcs Facilitates Recovery: Evidence for Modular Integration of ATM/ATR/DNA-PKcs Functions
| Autor: | Aashish Soni, Xiaolu Duan, Martin Stuschke, George Iliakis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
DSB end resection (resection)
Medizin Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins DNA-Activated Protein Kinase Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Strahlentherapie Genomic Instability Catalysis Inorganic Chemistry DNA-PK Radiation Ionizing Animals Humans ddc:610 Phosphorylation Physical and Theoretical Chemistry Molecular Biology Spectroscopy Mammals Organic Chemistry DNA Double Strand Breaks (DSB) ATM ATR intra-S-phase checkpoint ionizing radiation (IR) DNA General Medicine Computer Science Applications Medizinische Fakultät » Universitätsklinikum Essen » Institut für Medizinische Strahlenbiologie Checkpoint Kinase 1 DNA Damage |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 14; Pages: 7506 |
| Popis: | The intra-S-phase checkpoint was among the first reported cell cycle checkpoints in mammalian cells. It transiently slows down the rate of DNA replication after DNA damage to facilitate repair and thus prevents genomic instability. The ionizing radiation (IR)-induced intra-S-phase checkpoint in mammalian cells is thought to be mainly dependent upon the kinase activity of ATM. Defects in the intra-S-phase checkpoint result in radio-resistant DNA synthesis (RDS), which promotes genomic instability. ATM belongs to the PI3K kinase family along with ATR and DNA-PKcs. ATR has been shown to be the key kinase for intra-S-phase checkpoint signaling in yeast and has also been implicated in this checkpoint in higher eukaryotes. Recently, contributions of DNA-PKcs to IR-induced G₂-checkpoint could also be established. Whether and how ATR and DNA-PKcs are involved in the IR-induced intra-S-phase checkpoint in mammalian cells is incompletely characterized. Here, we investigated the contributions of ATM, ATR, and DNA-PKcs to intra-S-phase checkpoint activation after exposure to IR of human and hamster cells. The results suggest that the activities of both ATM and ATR are essential for efficient intra-S-phase checkpoint activation. Indeed, in a wild-type genetic background, ATR inhibition generates stronger checkpoint defects than ATM inhibition. Similar to G2 checkpoint, DNA-PKcs contributes to the recovery from the intra-S-phase checkpoint. DNA-PKcs–deficient cells show persistent, mainly ATR-dependent intra-S-phase checkpoints. A correlation between the degree of DSB end resection and the strength of the intra-S-phase checkpoint is observed, which again compares well to the G2 checkpoint response. We conclude that the organization of the intra-S-phase checkpoint has a similar mechanistic organization to that of the G₂ checkpoint in cells irradiated in the G₂ phase. OA Förderung 2022 |
| Databáze: | OpenAIRE |
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