A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response

Cell. 2014 May 8;157(4):869-81. doi: 10.1016/j.cell.2014.03.040.

Roman Alpatov ¹, Bluma J Lesch ², Mika Nakamoto-Kinoshita ³, Andres Blanco ¹, Shuzhen Chen ¹, Alexandra Stützer ⁴, Karim J Armache ⁵, Matthew D Simon ⁵, Chao Xu ⁶, Muzaffar Ali ⁷, Jernej Murn ¹, Sladjana Prisic ⁸, Tatiana G Kutateladze ⁷, Christopher R Vakoc ⁹, Jinrong Min ⁶, Robert E Kingston ⁵, Wolfgang Fischle ⁴, Stephen T Warren ³, David C Page ², Yang Shi ¹⁰

Affiliations

1 Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
2 Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
3 Departments of Human Genetics, Biochemistry, and Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
4 Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
5 Massachusetts General Hospital, Department of Molecular Biology and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
6 Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto ON M5G 1L7, Canada.
7 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
8 Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
9 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
10 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: [email protected].

PMID: 24813610 DOI: 10.1016/j.cell.2014.03.040

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.

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