title: Cell transcriptional state alters genomic patterns of DNA double-strand break repair in human astrocytes.
abstract: The misrepair of DNA double-strand breaks in close spatial proximity within the nucleus can result in chromosomal rearrangements that are important in the pathogenesis of haematopoietic and solid malignancies. It is unknown why certain epigenetic states, such as those found in stem or progenitor cells, appear to facilitate neoplastic transformation. Here we show that altering the transcriptional state of human astrocytes alters patterns of DNA damage repair from ionizing radiation at a gene locus-specific and genome-wide level. Astrocytes induced into a reactive state exhibit increased DNA repair, compared with non-reactive cells, in actively transcribed chromatin after irradiation. In mapping these repair sites, we identify misrepair events and repair hotspots that are unique to each state. The precise characterization of genomic regions susceptible to mutation in specific transcriptional states provides new opportunities for addressing clonal evolution in solid cancers, in particular those where double-strand break induction is a cornerstone of clinical intervention.
authors.affiliation: 1] Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, 1463 Madison Avenue, Box 1136, New York, New York 10029, USA [2] Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Raymund L
authors.initials: RL
authors.lastname: Yong
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.affiliation: 1] Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, 1463 Madison Avenue, Box 1136, New York, New York 10029, USA.
authors.forename: Huaien
authors.initials: H
authors.lastname: Wang
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Cody D
authors.initials: CD
authors.lastname: Schlaff
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Tandle
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Graves
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: 1] Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
mesh_terms: D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology / Q000528:radiation effects*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism / Q000528:radiation effects; D060965:Clonal Evolution; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005333:Fetus; D005720:Gamma Rays; D015870:Gene Expression; D015894:Genome, Human; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D009154:Mutation; D061251:Primary Cell Culture; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; D004247:DNA