Rucaparib Treatment Alters p53 Oscillations in Single Cells to Enhance DNA-Double-Strand-Break-Induced Cell Cycle Arrest
Autor: | Eric Batchelor, Ryan L. Hanson |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Indoles Cell cycle checkpoint DNA Repair DNA repair DNA damage Poly ADP ribose polymerase DNA-Activated Protein Kinase Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Zinostatin Humans DNA Breaks Double-Stranded Rucaparib Transcription factor Polymerase Cell Proliferation biology Cell Cycle Checkpoints Cell biology Enzyme Activation HEK293 Cells 030104 developmental biology Gene Expression Regulation chemistry MCF-7 Cells biology.protein Single-Cell Analysis Tumor Suppressor Protein p53 030217 neurology & neurosurgery DNA |
Zdroj: | Cell Rep |
ISSN: | 2211-1247 |
DOI: | 10.1016/j.celrep.2020.108240 |
Popis: | DNA double strand breaks induce oscillatory expression of the transcription factor p53 that is dependent on ataxia telangiectasia mutated (ATM) activity and the rate of double strand break resolution. Although p53 dynamics are known to play a role in the regulation of cell fate determination, the consequences of the variability in dynamics associated with differences in repair rates and utilized repair pathways are unknown. Using single-cell time-lapse microscopy, we found that disruption of specific repair pathways has distinct impacts on p53 dynamics. The small-molecule rucaparib, an inhibitor of the alternative end-joining-associated protein poly (ADP-ribose) polymerase (PARP), increased p53 pulse duration, altering the temporal expression of multiple p53 target genes. As a result, combination treatments of the radiomimetic drug neocarzinostatin with rucaparib drove prolonged growth arrest beyond that of DNA damage alone. This study highlights how pharmacological manipulation of DNA repair pathways may be used to alter p53 dynamics to enhance therapeutic regimens. |
Databáze: | OpenAIRE |
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