A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response

• Type of Material: Article
• Authors: Roman Alpatov, Boston Children’s Hospital; Bluma J. Lesch, Massachusetts Institute of Technology; Mika Nakamoto-Kinoshita, Emory University; Andres Blanco, Boston Children’s Hospital; Shuzhen Chen, Boston Children’s Hospital; Alexandra Stuetzer, Max Plank Institute for Biophysical Chemistry; Karim J. Armache, Harvard University; Matthew D. Simon, Harvard University; Chao Xu, University of Toronto; Muzaffar Ali, University of Colorado; Jernej Murn, Boston Children’s Hospital; Slandjana Prisic, Harvard University; Tatiana G. Kutateladze, University of Colorado; Christopher R. Vakoc, Cold Spring Harbor Laboratory; Jinrong Min, University of Toronto; Robert E. Kingston, Harvard University; Wolfgang Fischle, Max Plank Institute for Biophysical Chemistry; Stephen Warren, Emory University; David C. Page, Massachusetts Institute of Technology; Yang Shi, Boston Children’s Hospital
• Language: English
• Date: 2014-05-08
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2014.03.040
• Title of Journal or Parent Work: Analytical Cellular Pathology / Cellular Oncology
• ISSN: 1570-5870
• Volume: 157
• Issue: 4
• Start Page: 869
• End Page: 881
• Grant/Funding Information: Y.S. is an American Cancer Society Research Professor.; This work was supported by NCI118487 and MH080129 to Y.S.; by National Research Training Grant AG00222-7 to R.A; NRSA HD075591 to B.J.L.; by HHMI funding to D.C.P.; and in part by HD020521 and HD024064 to S.T.W. Y.S. is an American Cancer Society Research Professor.
• Keywords: DYNAMICS; MUTATION; DOMAIN; SURVIVAL; Biochemistry & Molecular Biology; TARGETS; Life Sciences & Biomedicine; TUDOR; Cell Biology; Science & Technology; BRCA1; MICE LACKING; H3K79 METHYLATION
• Research Categories: Biology, Genetics; Biology, Cell; Chemistry, Biochemistry

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.