title: Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum.
abstract: Maintenance of genomic integrity is critical during neurodevelopment, particularly in rapidly dividing cerebellar granule neuronal precursors that experience constitutive replication-associated DNA damage. As Dicer was recently recognized to have an unexpected function in the DNA damage response, we examined whether Dicer was important for preserving genomic integrity in the developing brain. We report that deletion of Dicer in the developing mouse cerebellum resulted in the accumulation of DNA damage leading to cerebellar progenitor degeneration, which was rescued with p53 deficiency; deletion of DGCR8 also resulted in similar DNA damage and cerebellar degeneration. Dicer deficiency also resulted in DNA damage and death in other rapidly dividing cells including embryonic stem cells and the malignant cerebellar progenitors in a mouse model of medulloblastoma. Together, these results identify an essential function of Dicer in resolving the spontaneous DNA damage that occurs during the rapid proliferation of developmental progenitors and malignant cells.
authors.affiliation: Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: swahari@email.unc.edu.
authors.forename: Vijay
authors.initials: V
authors.lastname: Swahari
authors.affiliation: Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baran-Gale
authors.affiliation: Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Idoia
authors.initials: I
authors.lastname: Garcia
authors.affiliation: Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Crowther
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sons
authors.affiliation: Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Hammond
authors.affiliation: Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Sethupathy
authors.affiliation: Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: mohanish@med.unc.edu.
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism*
chemical_list: C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: apoptosis; dicer; embryonic stem cells; medulloblastoma; p53; replicative stress