title: DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis.
abstract: 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.
  
  
  
  The DNA damage response (DDR) is essential for prevention of a broad spectrum of different human neurologic diseases. However, a detailed understanding of the DDR at a physiological level is lacking. In contrast to many in vitro cellular studies, here we demonstrate independent biological roles for the DDR kinases DNA-PKcs, ATM, and ATR during neurogenesis. We show that DNA-PKcs is central to DNA repair in nonproliferating cells, and restricts DNA damage accumulation, whereas ATR controls damage-induced G2checkpoint control and apoptosis in proliferating cells. Conversely, ATM is critical for controlling apoptosis in immature noncycling neural cells after DNA damage. These data demonstrate functionally distinct, but cooperative, roles for each kinase in preserving genome stability in the nervous system.
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105.|College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, and.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Enriquez-Rios
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Lavinia C
authors.identifier: 0000-0001-7616-3365
authors.initials: LC
authors.lastname: Dumitrache
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Susanna M
authors.identifier: 0000-0002-6773-7838
authors.initials: SM
authors.lastname: Downing
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Abramson Family Cancer Research Institute and the Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Russell
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, peter.mckinnon@stjude.org.|College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016678:Genome / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse
keywords: ATM; ATR; DNA damage; DNA-Pkcs; genome stability; neurogenesis