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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)869-881
Number of pages13
JournalCell
Volume157
Issue number4
DOIs
StatePublished - May 8 2014
Externally publishedYes

Bibliographical note

Funding Information:
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; and 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 Dot1L fl/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; 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. This work was supported by NIH grants NCI118487 and MH096066 to Y.S., National Research Training Grant AG00222-7 to R.A., NRSA grant HD075591 and a Hope Funds for Cancer Research postdoctoral fellowship to B.J.L., and HHMI funding to D.C.P., and in part by NIH grants HD020521 and HD024064 to S.T.W. Y.S. is an American Cancer Society Research Professor, and is a cofounder of Constellation Pharmaceuticals and a member of its scientific advisory board.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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