title: Long Neural Genes Harbor Recurrent DNA Break Clusters in Neural Stem/Progenitor Cells.
abstract: Repair of DNA double-strand breaks (DSBs) by non-homologous end joining is critical for neural development, and brain cells frequently contain somatic genomic variations that might involve DSB intermediates. We now use an unbiased, high-throughput approach to identify genomic regions harboring recurrent DSBs in primary neural stem/progenitor cells (NSPCs). We identify 27 recurrent DSB clusters (RDCs), and remarkably, all occur within gene bodies. Most of these NSPC RDCs were detected only upon mild, aphidicolin-induced replication stress, providing a nucleotide-resolution view of replication-associated genomic fragile sites. The vast majority of RDCs occur in long, transcribed, and late-replicating genes. Moreover, almost 90% of identified RDC-containing genes are involved in synapse function and/or neural cell adhesion, with a substantial fraction also implicated in tumor suppression and/or mental disorders. Our characterization of NSPC RDCs reveals a basis of gene fragility and suggests potential impacts of DNA breaks on neurodevelopment and neural functions.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wei
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Amelia N
authors.initials: AN
authors.lastname: Chang
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kao
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Du
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Meyers
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: alt@enders.tch.harvard.edu.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bjoern.schwer@childrens.harvard.edu.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Schwer
mesh_terms: D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins; D001921:Brain / Q000166:cytology; D002448:Cell Adhesion; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D053960:DNA Breaks / Q000187:drug effects; D059766:DNA End-Joining Repair; D004260:DNA Repair; D058851:GPI-Linked Proteins / Q000378:metabolism; D016678:Genome; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D013569:Synapses; D014157:Transcription Factors / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D016590:Aphidicolin; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C502963:NPAS3 protein, human; C095362:limbic system-associated membrane protein