ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation.
Microcephaly and medulloblastoma may both result from mutations that compromise genomic stability. We report that ATR, which is mutated in the microcephalic disorder Seckel syndrome, sustains cerebellar growth by maintaining chromosomal integrity during postnatal neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis and cerebellar hypoplasia in mice. Co-deletions of either p53 or Bax and Bak prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. ATR-deficient CGNPs had impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to ATR-deficient proliferation was highly p53 dependent and markedly attenuated by p53 co-deletion. Acute ATR inhibition in vivo by nanoparticle-formulated VE-822 reproduced the developmental disruptions seen with Atr deletion. Genetic deletion of Atr blocked tumorigenesis in medulloblastoma-prone SmoM2 mice. Our data show that p53-driven apoptosis and cell cycle arrest - and, in the absence of p53, non-apoptotic cell death - redundantly limit growth in ATR-deficient progenitors. These mechanisms may be exploited for treatment of CGNP-derived medulloblastoma using ATR inhibition.
Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.|Department of Neurology, UNC School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Patrick Y
PY
Lang
Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Research Center, New York, NY 10021, USA.
Gouri J
GJ
Nanjangud
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Marina
M
Sokolsky-Papkov
Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Research Center, New York, NY 10021, USA.
Christine
C
Shaw
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Duhyeong
D
Hwang
Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Joel S
JS
Parker
Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Alexander V
AV
Kabanov
Department of Neurology, UNC School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA gershont@neurology.unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.|Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Timothy R
0000-0001-7034-6400
TR
Gershon
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D043171:Chromosomal Instability / Q000187:drug effects / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009421:Nervous System Malformations / Q000235:genetics / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology
D007555:Isoxazoles; D011719:Pyrazines; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C000598331:berzosertib
ATR; Chromosomal instability; DNA damage; Medulloblastoma; Microcephaly; Mouse; Neural progenitor