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Author Notes:

Yang Shi: yang_shi@hms.harvard.edu.

List of author contributions available in full text.

We thank S. Elledge and B. Yankner for advice and helpful suggestions; A. Ciccia for help with DNA damage experiments; D. Reinberg and P. Voigt for help with nucleosomal preparations; J. Griesbach, A. Lazic, and S. Duhr from NanoTemper Technologies and K. Yamagata, Y. Zheng and X. Shang for help with microscale thermophoresis and kinetic data analysis; E. Greer, A. Alekseyenko and G. Shanower for logistical support.

We also thank J. Mowrey, S. Ceman, S. Keeney, and U. Fischer for reagents; M. Bear for Fmr1 KO mice; S. Armstrong for Dot1Lfl/fl mice; K. Luger, G. Narlikar, S. Ceman and U. Fischer for helpful comments; and M. Goodheart, D. Cooper, E. Derby, L. Elow, K. Igarashi, L. Kolinski, L. Pomponi, and M. Schuck for technical assistance.

We also thank our collaborators who contributed to this project but whose work was not included in the manuscript: B. Ren, U. Wagner and the Ren laboratory for FMRP genome-wide analysis and K. Zhao and his group for H3K79me2 genome-wide analysis; A. Vaquero for Suv39h double null MEFs; and G. Schotta and T. Jenuwein for Suv4-20h double null MEFs.

Y.S. is a co-founder of Constellation Pharmaceuticals and a member of its advisory board.

Subjects:

Research Funding:

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.

Y.S. is an American Cancer Society Research Professor.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • H3K79 METHYLATION
  • MICE LACKING
  • DYNAMICS
  • TARGETS
  • BRCA1
  • SURVIVAL
  • MUTATION
  • DOMAIN
  • TUDOR

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

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Journal Title:

Analytical Cellular Pathology / Cellular Oncology

Volume:

Volume 157, Number 4

Publisher:

, Pages 869-881

Type of Work:

Article | Post-print: After Peer Review

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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© 2014 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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