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The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and DNA repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit of the DNA-dependent kinase, encoded by PRKDC), ATM (ataxia telangiectasia, mutated), and ATR (ATM and Rad3-related) are related PI3K-like protein kinases and central regulators of the DDR. Defects in these kinases have been linked to neurodegenerative or neurodevelopmental syndromes. In all cases, the key neuroprotective function of these kinases is uncertain. It also remains unclear how interactions between the three DNA damage-responsive kinases coordinate genome stability, particularly in a physiological context. Here, we used a genetic approach to identify the neural function of DNA-PKcs and the interplay between ATM and ATR during neurogenesis. We found that DNA-PKcs loss in the mouse sensitized neuronal progenitors to apoptosis after ionizing radiation because of excessive DNA damage. DNA-PKcs was also required to prevent endogenous DNA damage accumulation throughout the adult brain. In contrast, ATR coordinated the DDR during neurogenesis to direct apoptosis in cycling neural progenitors, whereas ATM regulated apoptosis in both proliferative and noncycling cells. We also found that ATR controls a DNA damage-induced G2/M checkpoint in cortical progenitors, independent of ATM and DNA-PKcs. These nonoverlapping roles were further confirmed via sustained murine embryonic or cortical development after all three kinases were simultaneously inactivated. Thus, our results illustrate how DNA-PKcs, ATM, and ATR have unique and essential roles during the DDR, collectively ensuring comprehensive genome maintenance in the nervous system.
Pubmed ID: 28123024 RIS Download
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This polyclonal targets ACTG1, ACTC1, ACTA1, ACTA2, ACTG2, ACTB
View all literature mentionsThis polyclonal targets KAP1
View all literature mentionsThis unknown targets Phospho-KAP-1 (Ser824)
View all literature mentionsThis monoclonal targets ATM (D2E2) Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-p53 (Ser15)
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View all literature mentionsThis polyclonal targets ATM, phospho (Ser1981)
View all literature mentionsThis monoclonal targets DNA-PKcs (DNA-Repair Enzyme & Apoptosis Marker)
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View all literature mentionsThis monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis polyclonal targets Phospho-Histone H3 (Ser10)
View all literature mentionsThis polyclonal targets Phospho-Histone H2A.X (Ser139)
View all literature mentionsThis monoclonal targets Caspase 3, Active Form
View all literature mentionsThis monoclonal targets Ctip2
View all literature mentionsThis polyclonal targets Mouse TBR2 / Eomes
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsMus musculus with name B6.129S2-Emx1tm1(cre)Krj/J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-Tg(Nes-cre)1Kln/J from IMSR.
View all literature mentionsThis polyclonal targets ACTG1, ACTC1, ACTA1, ACTA2, ACTG2, ACTB
View all literature mentionsThis polyclonal targets KAP1
View all literature mentionsThis unknown targets Phospho-KAP-1 (Ser824)
View all literature mentionsThis monoclonal targets ATM (D2E2) Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-p53 (Ser15)
View all literature mentionsThis monoclonal targets CHEK2
View all literature mentionsThis polyclonal targets ATM, phospho (Ser1981)
View all literature mentionsThis monoclonal targets DNA-PKcs (DNA-Repair Enzyme & Apoptosis Marker)
View all literature mentionsThis unknown targets
View all literature mentionsThis unknown targets
View all literature mentionsThis unknown targets
View all literature mentionsThis unknown targets
View all literature mentionsThis monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis polyclonal targets Phospho-Histone H3 (Ser10)
View all literature mentionsThis polyclonal targets Phospho-Histone H2A.X (Ser139)
View all literature mentionsThis monoclonal targets Caspase 3, Active Form
View all literature mentionsThis monoclonal targets Ctip2
View all literature mentionsThis polyclonal targets Mouse TBR2 / Eomes
View all literature mentionsMus musculus with name B6.129S2-Emx1tm1(cre)Krj/J from IMSR.
View all literature mentionsMus musculus with name B6.Cg-Tg(Nes-cre)1Kln/J from IMSR.
View all literature mentionsThis monoclonal targets Ctip2
View all literature mentionsThis monoclonal targets Caspase 3, Active Form
View all literature mentionsThis polyclonal targets Mouse TBR2 / Eomes
View all literature mentionsMus musculus with name B6.Cg-Tg(Nes-cre)1Kln/J from IMSR.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsThis unknown targets
View all literature mentionsThis monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis unknown targets
View all literature mentionsThis polyclonal targets Phospho-Histone H3 (Ser10)
View all literature mentionsThis polyclonal targets Phospho-Histone H2A.X (Ser139)
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsThis polyclonal targets ATM, phospho (Ser1981)
View all literature mentionsThis polyclonal targets Phospho-p53 (Ser15)
View all literature mentionsThis monoclonal targets DNA-PKcs (DNA-Repair Enzyme & Apoptosis Marker)
View all literature mentionsThis unknown targets
View all literature mentionsThis monoclonal targets ATM (D2E2) Rabbit mAb
View all literature mentionsThis unknown targets Phospho-KAP-1 (Ser824)
View all literature mentionsThis polyclonal targets KAP1
View all literature mentionsThis monoclonal targets CHEK2
View all literature mentionsThis polyclonal targets ACTG1, ACTC1, ACTA1, ACTA2, ACTG2, ACTB
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsThis unknown targets
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