title: A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.
abstract: Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Alpatov
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Bluma J
authors.initials: BJ
authors.lastname: Lesch
authors.affiliation: Departments of Human Genetics, Biochemistry, and Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Nakamoto-Kinoshita
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Blanco
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stützer
authors.affiliation: Massachusetts General Hospital, Department of Molecular Biology and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Karim J
authors.initials: KJ
authors.lastname: Armache
authors.affiliation: Massachusetts General Hospital, Department of Molecular Biology and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Simon
authors.affiliation: Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto ON M5G 1L7, Canada.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Ali
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jernej
authors.initials: J
authors.lastname: Murn
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sladjana
authors.initials: S
authors.lastname: Prisic
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.affiliation: Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto ON M5G 1L7, Canada.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Min
authors.affiliation: Massachusetts General Hospital, Department of Molecular Biology and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Kingston
authors.affiliation: Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischle
authors.affiliation: Departments of Human Genetics, Biochemistry, and Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Page
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: yang_shi@hms.harvard.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D023902:Chromosome Pairing; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008540:Meiosis; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011418:Prophase; D018091:Receptors, AMPA / Q000378:metabolism; D013091:Spermatogenesis
chemical_list: D002843:Chromatin; D051860:Fragile X Messenger Ribonucleoprotein 1; D006657:Histones; D018091:Receptors, AMPA; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse; C475961:gamma-H2AX protein, mouse